Efficacy and Safety of Acupuncture for Restless Legs Syndrome in Patients with End-Stage Renal Disease: A Randomized-Controlled Trial at Hospital-Based Hemodialysis Center.

Background: Restless legs syndrome (RLS) is frequent in patients with hemodialysis (HD) and occurs predominantly in its most severe forms. The study was conducted to evaluate the efficacy and safety of acupuncture for RLS in patients with end-stage renal disease (ESRD) at hospital-based HD center. Methods: This single-blind, randomized controlled trial was performed on patients with HD and RLS who were randomly assigned to the experimental group and control group. Data were collected using the International Restless Legs Syndrome Rating Scale (IRLSRS), Insomnia Severity Index (ISI), and heart rate variability (HRV) records at baseline, after the therapeutic course (12 times/4 weeks), and 1-week follow-up. Result: A total of 47 patients were evaluated with IRLSRS score from 11 to 30 in this study. There were 41 patients enrolled in the study based on inclusion/exclusion criteria and allocated randomly into two groups. A total of 35 participants completed the trial, including 18 subjects in the experimental group and 17 subjects in the control group. The comparison of IRLSRS and ISI showed a significant reduction between two groups after acupuncture treatment (p = 0.002, p = 0.003). The ISI after 1-week follow-up also revealed significant decrease (p = 0.003). This HRV results showed that high frequency (HF%) increased significantly (p = 0.021) and low frequency (LF%) decreased significantly in the acupuncture group (p = 0.021). The generalized estimating equation showed that the IRLSRS improved by 2.902 points (p < 0.001) in the acupuncture group compared with the control group and by 1.340 points (p = 0.003) after 1-week follow-up. There were no adverse effects observed during HD in this study. Discussion: The authors conclude that acupuncture could effectively improve the symptoms of RLS significantly. The results from this study provide clinical evidence on the efficacy and safety of acupuncture to treat the patients with RLS at the HD center.

Traumatic brain injury and risk of heart failure and coronary heart disease: A nationwide population-based cohort study.

BACKGROUND: This study examined the long-term risks of heart failure (HF) and coronary heart disease (CHD) following traumatic brain injury (TBI), focusing on gender differences. METHODS: Data from Taiwan's National Health Insurance Research Database included 29,570 TBI patients and 118,280 matched controls based on propensity scores. RESULTS: The TBI cohort had higher incidences of CHD and HF (9.76 vs. 9.07 per 1000 person-years; 4.40 vs. 3.88 per 1000 person-years). Adjusted analyses showed a significantly higher risk of HF in the TBI group (adjusted hazard ratio = 1.08, 95% CI = 1.01-1.17, P = 0.031). The increased CHD risk in the TBI cohort became insignificant after adjustment. Subgroup analysis by gender revealed higher HF risk in men (aHR = 1.14, 95% CI = 1.03-1.25, P = 0.010) and higher CHD risk in women under 50 (aHR = 1.32, 95% CI = 1.15-1.52, P < 0.001). TBI patients without beta-blocker therapy may be at increased risk of HF. CONCLUSION: Our results suggest that TBI increases the risk of HF and CHD in this nationwide cohort of Taiwanese citizens. Gender influences the risks differently, with men at higher HF risk and younger women at higher CHD risk. Beta-blockers have a neutral effect on HF and CHD risk.

Effects of insomnia and non-vasomotor menopausal symptoms on coronary heart disease risk: a mendelian randomization study.

Background: Previous studies suggested that vasomotor symptoms were associated with an increasing risk of coronary heart diseases (CHD) but not clear with menopausal symptoms other than vasomotor symptoms. Given the heterogeneity and interrelationship among menopausal symptoms, it is not easy to make causal inferences based on observational studies. We performed a Mendelian randomization (MR) to investigate the association of individual non-vasomotor menopausal symptoms and the risk of CHDs. Methods: A sample of 177,497 British women aged ≥51 years old (average age at menopause) without related cardiovascular diseases from the UK biobank is selected as our study population. Non-vasomotor menopausal symptoms, including anxiety, nervous, insomnia, urinary tract infection, fatigue, and vertigo, were selected as exposures based on the modified Kupperman index. Outcome variable is CHD. Results: In total, 54, 47, 24, 33, 22, and 81 instrumental variables were selected for anxiety, insomnia, fatigue, vertigo, urinary tract infection and nervous respectively. We conducted MR analyses of menopausal symptoms and CHD. Only insomnia symptoms increased the lifetime risk of CHD with OR 1.394 (p = 0.0003). There were no significant causal relationships with CHD and other menopausal symptoms. Insomnia near menopause age (45-50 years) does not increase the risk of CHD. However, postmenopausal (over 51) insomnia increases the risk of CHD. Conclusion: MR analyses support that among non-vasomotor menopausal symptoms, only insomnia symptoms may increase the lifetime risk of CHD. Insomnia at different ages near menopause has differential impacts on CHD risk.

The MicroRNA Prediction Models as Ancillary Diagnosis Biomarkers for Urothelial Carcinoma in Patients With Chronic Kidney Disease.

Urothelial carcinoma is a common urological cancer in chronic kidney disease patients. Cystoscopy and urine cytology are the clinical diagnostic tools for UC. However, cystoscopy is an invasive procedure, while urine cytology showed low sensitivity for low-grade urothelial tumors. High accuracy with non-invasive tools for UC is needed for CKD patients. Our study collected a total of 272 urine and 138 plasma samples to detect the miRNA expression levels for establishing UC signatures from CKD patients. Seventeen candidate miRNAs of biofluids were selected and confirmed by qRT-PCR. Our results showed that urinary miR-1274a and miR-30a-5p expression levels were significantly lower but miR-19a-5p expression levels were higher in UC when compared with CKD. In plasma samples, miR-155-5p, miR-19b-1-5p, miR-378, and miR-636 showed significantly lower expression in UC compared to those with CKD. The Kaplan-Meier curve showed that lower expression of miR-19a, miR-19b, miR-636 and miR-378, and higher expression of miR-708-5p were associated with poor prognosis in patients with bladder cancer. In addition, we produced classifiers for predicting UC by multiple logistic regression. The urine signature was developed with four miRNAs, and the AUC was 0.8211. Eight miRNA expression levels from both urine and plasma samples were examined, and the AUC was 0.8595. Two miRNA classifiers and the nomograms could improve the drawbacks of current UC biomarker screenings for patients with CKD.

Machine Learning Analysis of Time-Dependent Features for Predicting Adverse Events During Hemodialysis Therapy: Model Development and Validation Study.

BACKGROUND: Hemodialysis (HD) therapy is an indispensable tool used in critical care management. Patients undergoing HD are at risk for intradialytic adverse events, ranging from muscle cramps to cardiac arrest. So far, there is no effective HD device-integrated algorithm to assist medical staff in response to these adverse events a step earlier during HD. OBJECTIVE: We aimed to develop machine learning algorithms to predict intradialytic adverse events in an unbiased manner. METHODS: Three-month dialysis and physiological time-series data were collected from all patients who underwent maintenance HD therapy at a tertiary care referral center. Dialysis data were collected automatically by HD devices, and physiological data were recorded by medical staff. Intradialytic adverse events were documented by medical staff according to patient complaints. Features extracted from the time series data sets by linear and differential analyses were used for machine learning to predict adverse events during HD. RESULTS: Time series dialysis data were collected during the 4-hour HD session in 108 patients who underwent maintenance HD therapy. There were a total of 4221 HD sessions, 406 of which involved at least one intradialytic adverse event. Models were built by classification algorithms and evaluated by four-fold cross-validation. The developed algorithm predicted overall intradialytic adverse events, with an area under the curve (AUC) of 0.83, sensitivity of 0.53, and specificity of 0.96. The algorithm also predicted muscle cramps, with an AUC of 0.85, and blood pressure elevation, with an AUC of 0.93. In addition, the model built based on ultrafiltration-unrelated features predicted all types of adverse events, with an AUC of 0.81, indicating that ultrafiltration-unrelated factors also contribute to the onset of adverse events. CONCLUSIONS: Our results demonstrated that algorithms combining linear and differential analyses with two-class classification machine learning can predict intradialytic adverse events in quasi-real time with high AUCs. Such a methodology implemented with local cloud computation and real-time optimization by personalized HD data could warn clinicians to take timely actions in advance.

Menopausal symptoms and risk of heart failure: a retrospective analysis from Taiwan National Health Insurance Database.

AIMS: Women with menopausal symptoms show evidence of accelerated epigenetic ageing, vascular aging and low-grade systemic inflammation status. However, data are limited regarding menopausal symptoms and risk of heart failure (HF). We aimed to explore the impact of menopausal symptoms on risk of HF. METHODS: We included 14 340 symptomatic menopausal women without a history of coronary heart disease (CHD) or HF from the Taiwan National Health Insurance Research Database as the experimental cohort. We included 14 340 asymptomatic women matched for age and comorbidities as controls. We surveyed possible comorbidity-attributable risks of HF and assessed whether menopausal symptoms play a role in risk of HF. Additional analyses were conducted to ascertain the association of CHD and HF in different risk factor burdens categories in both cohorts and CHD was applied as a sensitivity analysis. RESULTS: The incidence of HF was not significantly lower in the experimental than in the control cohort (4.87 vs. 5.06 per 1000 person-years, P = 0.336). Participants with a higher comorbidity burden had a proportionally increased risk of HF and CHD in both cohorts. The burden of risk factors had a greater impact on risk of HF in the control than in the experimental cohort (≥five risk factors, adjusted hazard ratio 25.69 vs. 14.75). Participants undergoing hormone therapy had no significant effect on the risk of HF, regardless of the presence or absence of menopausal symptoms. Subgroup analysis revealed that compared with the control cohort, the risk of HF in the experimental cohort did not increase significantly in all subgroups. CONCLUSIONS: Menopausal symptoms were associated with CHD risk but not with risk of HF. Traditional risk factors rather than menopausal symptoms play important roles in the HF risk among middle-aged women.

The tongue features associated with chronic kidney disease.

BACKGROUND: Traditional Chinese medicine (TCM) tongue diagnosis plays an important role in differentiation of symptoms because the tongue reflects the physiological and pathological condition of the body. The automatic tongue diagnosis system (ATDS), which noninvasively captures tongue images, can provide objective and reliable diagnostic information. Chronic kidney disease (CKD) currently is an important global public health problem and contributor to morbidity and mortality from non-communicable diseases. Thus, it is interesting to analyze and probe the relationship between tongue examination and CKD. METHODS: This protocol is a cross-sectional, case-controlled observational study investigating the usefulness of the ATDS in clinical practice by examining its efficacy as a diagnostic tool for CKD. Volunteers over 20 years old with and without CKD will be enrolled. Tongue images will be captured and the patients divided into 2 groups: CKD group and healthy group. Nine primary tongue features will be extracted and analyzed, including tongue shape, tongue color, tooth mark, tongue fissure, fur color, fur thickness, saliva, ecchymosis, and red dots. RESULT: The results of this study will systematically evaluate tongue manifestations of patients and examine its efficacy as an early detection and diagnosis of CKD. DISCUSSION: The aim of this protocol is to investigate discriminating tongue features to distinguish between CKD and normal people, and establish differentiating index to facilitate the noninvasive detection of CKD. TRIAL REGISTRIES: ClinicalTrials.gov; Identifier: NCT04708743.

Discovery of Novel Protein Biomarkers in Urine for Diagnosis of Urothelial Cancer Using iTRAQ Proteomics.

Urothelial carcinoma (UC) is the ninth most prevalent malignancy worldwide. Noninvasive and efficient biomarkers with high accuracy are imperative for the surveillance and diagnosis of UC. CKD patients were enrolled as a control group in this study for the discovery of highly specific urinary protein markers of UC. An iTRAQ-labeled quantitative proteomic approach was used to discover novel potential markers. These markers were further validated with 501 samples by ELISA assay, and their diagnostic accuracies were compared to those of other reported UC markers. BRDT, CYBP, GARS, and HDGF were identified as novel urinary UC biomarkers with a high discrimination ability in a population comprising CKD and healthy subjects. The diagnostic values of the four novel UC markers were better than that of a panel of well-known or FDA-approved urinary protein markers CYFR21.1, Midkine, and NUMA1. Three of our discovered markers (BRDT, HDGF, GARS) and one well-known marker (CYFR21.1) were finally selected and combined as a marker panel having AUC values of 0.962 (95% CI, 0.94-0.98) and 0.860 (95% CI, 0.83-0.89) for the discrimination between UC and normal groups and UC and control (healthy + CKD) groups, respectively.

Urine phthalate metabolites are associated with urothelial cancer in chronic kidney disease patients.

BACKGROUND: Di(2-ethylhexyl) phthalate (DEHP) is one of the most widely used phthalates and is associated with breast cancer. Ths association between DEHP and other types of cancer is not clear. DEHP may increase matrix metalloproteinase-9 that is critical for the development of urothelial cancer (UC). We examined the association between urinary phthalate metabolites and UC. CKD patients were selected as a control group because CKD patients are more at risk of UC than the general population. METHODS: In this cross-sectional study, we measured seven urinary phthalate metabolites that are abundant and can be measured using HPLC-MS/MS in Taiwan CKD patients between Jul 2013 and Dec 2015. MiBP (a urinary metabolite of Dibutyl phthalates[DBP]) and MEHHP (a urinary metabolite of DEHP) were described because they are the most abundant phthalate metabolites. The association of phthalate (log-transformed) and UC were analyzed using logistic regression with adjustments for age, gender, renal function, use of traditional Chinese medicine, toxins (dye, organic solvent), and non-steroidal anti-inflammatory drugs. RESULTS: We measured the urinary MEHHP and MiBP of 496 patients (224 UC and 272 CKD patients). The urinary MEHHP was associated with UC but MiBP was not. Medical history including the use of non-steroid anti-inflammatory drugs, exposure to environmental toxins (dye, paint, and organic solvent), and the use of traditional Chinese medicine was independently associated with UC. The adjusted odds ratio of MEHHP was 1.42 (95% confidence interval: 1.21-1.68). CONCLUSION: Phthalate urinary metabolite(MEHHP) may be associated with UC in CKD patients and the association is independent of well-known risk factors of UC.

Effect of electroacupuncture on restless legs syndrome (RLS) in hemodialysis patients: A protocol for systematic review and meta-analysis.

BACKGROUND: Restless legs syndrome (RLS) is frequent in dialysis patients and occurs predominantly in its most severe forms. The aim of the present study was to evaluate the effects of electroacupuncture (EA) in hemodialysis patients with RLS by heart rate variability (HRV) monitor. METHODS: One hundred twelve subjects who were hemodialysis patients with RLS will be divided into 2 groups: experimental and control. Each subject will receive the treatment relevant to their group 2 times a week for 4 weeks. After 4 weeks of treatment the subject will enter a 2-week washout period, after which the subjects will switch groups. Measurements will include HRV recordings, International Restless Legs Syndrome Rating Scale (IRLSRS) and Insomnia Severity Index (ISI). RESULT: The results of this study will systematically evaluate the effectiveness and safety of electoracupuncture intervention for hemodialysis patients with RLS. DISCUSSION: This study is the first investigation to analyze the relationship between EA and the change of HRV by an objective monitor. If the findings of the current trial are positive, this study will also help support an effective, safe and cheap approach to clinical treatment of this challenging disorder, help foster improved understanding the relationship between autonomic nervous system and RLS, and ultimately contribute to elucidate the mechanisms of EA. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04356794; registration date: April 22, 2020.

Tubular transcriptional co-activator with PDZ-binding motif protects against ischemic acute kidney injury.

Transcriptional co-activator with PDZ-binding motif (TAZ) is a key downstream effector of the Hippo tumor-suppressor pathway. The functions of TAZ in the kidney, especially in tubular epithelial cells, are not well-known. To elucidate the adaptive expression, protective effects on kidney injury, and signaling pathways of TAZ in response to acute kidney injury (AKI), we used in vitro (hypoxia-treated human renal proximal tubular epithelial cells [RPTECs]) and in vivo (mouse ischemia-reperfusion injury [IRI]) models of ischemic AKI. After ischemic AKI, TAZ was up-regulated in RPTECs and the renal cortex or tubules. Up-regulation of TAZ in RPTECs subjected to hypoxia was controlled by IκB kinase (IKK)/nuclear factor κ-light-chain-enhancer of activated B cell (NF-κB) signaling. TAZ overexpression attenuated hypoxic and oxidative injury, inhibited apoptosis and activation of p38 and c-Jun N-terminal kinase (JNK) proteins, and promoted wound healing in an RPTEC monolayer. However, TAZ knockdown aggravated hypoxic injury, apoptosis, and activation of p38 and JNK signaling, delayed wound closure of an RPTEC monolayer, and promoted G0/G1 phase cell-cycle arrest. Chloroquine and verteporfin treatment produced similar results to TAZ overexpression and knockdown in RPTECs, respectively. Compared with vehicle-treated mice, chloroquine treatment increased TAZ in the renal cortex and tubules, improved renal function, and attenuated tubular injury and tubular apoptosis after renal IRI, whereas TAZ siRNA and verteporfin decreased TAZ in the renal cortex and tubules, deteriorated renal failure and tubular injury, and aggravated tubular apoptosis. Our findings indicate the renoprotective role of tubular TAZ in ischemic AKI. Drugs augmenting (e.g., chloroquine) or suppressing (e.g., verteporfin) TAZ in the kidney might be beneficial or deleterious to patients with AKI.

Risk of venous thromboembolism in elderly patients with vertebral compression fracture: A population-based case-control study.

Vertebral compression fractures (VCFs) are common in elderly and are treated with immobilization. Moreover, immobilization and old age may increase venous thromboembolism (VTE) risk. However, the incidence of VCFs-related VTE is unknown in elderly. The purposes of this study were to determine the incidence of VTE among VCF patients, to explore whether percutaneous vertebroplasty (PV) intervention may reduce VTE risk in VCFs patients.We conducted a population-based case-control study by using the National Health Insurance Research Database. We identified 1407 patients aged ≥65 with VCF who received PV and 1407 VCFs patients who did not receive PV after developing a 1:1 propensity score-matched study cohort and were followed up for 5 years. Using PV intervention as the exposure factor, a cause-specific Cox's proportional hazards model was used to examine the association between PV and VTE.After propensity score matching, the mean age of the study participants was 78 years and ∼23% of the analyzed participants were men, incidence of VTE in the PV and control cohorts was 5.77 and 4.19 per 1000 person-years, respectively. Both groups were nonsignificant difference after examination with different adjustment models. Patients with VCF and a history of heart failure, coronary artery disease, receiving antihypertension medication were at a significantly increased VTE risk.Elderly patients with VCF who received PV had a neutral impact on risk of VTE. VCF patients with heart failure, coronary artery disease, and receiving antihypertension medication were prone to developing VTE should be monitored cautiously.

Symptomatic menopausal transition and risk of subsequent stroke.

OBJECTIVE: To examine the long-term risk of stroke in women who have experienced symptomatic menopausal transition. METHODS: In this nationwide, population-based cohort study conducted from January 1, 2000 to December 31, 2013, we identified 22,058 women with no prior history of stroke, who experienced symptomatic menopausal transition at ≥45 years of age. Moreover, 22,058 women without symptomatic menopause were matched by propensity scores and enrolled as a comparison group. The propensity score was calculated by using all characteristic variables of each subject, including demographics (age and monthly income), comorbidities (hypertension, hyperlipidemia, diabetes mellitus, obesity, chronic kidney disease, coronary artery disease, congestive heart failure, chronic obstructive pulmonary disease, dysrhythmia, peripheral artery occlusive disease), Charlson's comorbidity index score, clinic visit frequency, and long-term medications (antihypertensives, antidiabetic agents, statins, antiplatelets, aspirin, warfarin, and hormone replacement therapy). The primary endpoint was the development of stroke after the onset of symptomatic menopausal transition. The Fine and Gray's proportional subhazards model was performed to assess the association between symptomatic menopausal transition and subsequent stroke. All subjects were followed up until December 31, 2013. RESULTS: During a mean follow-up of 8.5 years (standard deviation 4.7 years, maximum 14 years), 2,274 (10.31%) women with symptomatic menopausal transition, and 1,184 (5.37%) matched comparison participants developed stroke. The incidence rates were 11.17 per 1,000 person-years in the symptomatic menopausal transition group compared with 8.57 per 1,000 person-years in the comparison group. The risk of developing stroke was significantly higher in women with symptomatic menopausal transition (crude subhazard ratio, 1.31; 95% confidence interval (CI) [1.22-1.41]; P < 0.001). After adjusting for demographics, comorbidities, clinic visit frequency, and long-term medications, the risk of stroke remained statistically significant (adjusted subhazard ratio, 1.30; 95% CI [1.21-1.40]; P < 0.001). Moreover, subgroup analyses revealed no evidence for inconsistent effects for symptomatic menopausal transition on subsequent risk of stroke across all subgroups except age, comorbidities, hypertension, and use of antihypertensives. Women with early menopausal transition (before age 50), without comorbid condition, without hypertension, or without use of antihypertensives are at a higher risk of stroke. The longer duration of symptomatic menopausal transition was associated with higher risk of stroke (P for trend < 0.001). CONCLUSION: In this large-scale retrospective cohort study, symptomatic menopausal transition was statistically significantly associated with a 30% increased risk of stroke. Further prospective studies are required to confirm our findings.

Urinary cell-free mitochondrial and nuclear deoxyribonucleic acid correlates with the prognosis of chronic kidney diseases.

INTRODUCTION: Cell-free deoxyribonucleic acid DNA (cf-DNA) in urine is promising due to the advantage of urine as an easily obtained and non-invasive sample source over tissue and blood. In clinical practice, it is important to identify non-invasive biomarkers of chronic kidney disease (CKD) in monitoring and surveillance of disease progression. Information is limited, however, regarding the relationship between urine and plasma cf-DNA and the renal outcome in CKD patients. METHODS: One hundred and thirty-one CKD patients were enrolled between January 2016 and September 2018. Baseline urine and plasma cell-free mitochondrial DNA (cf-mtDNA) and cell-free nuclear DNA (cf-nDNA) were isolated using quantitative real-time PCR. Estimated glomerular filtration rate (eGFR) measurement was performed at baseline and 6-month follow-up. Favorable renal outcome was defined as eGFR at 6 months minus baseline eGFR> = 0. Receiver operator characteristics (ROC) curve analysis was performed to assess different samples of cf-DNA to predict favorable renal outcomes at 6 months. A multivariate linear regression model was used to evaluate independent associations between possible predictors and different samples of cf-DNA. RESULTS: Patients with an advanced stage of CKD has significantly low plasma cf-nDNA and high plasma neutrophil gelatinase-associated lipocalin (NGAL) levels. Low urine cf-mtDNA, cf-nDNA levels and low plasma NGAL were significantly correlated with favorable renal outcomes at 6 months. The urine albumin-creatinine ratio (ACR) or urine protein-creatinine ratio (PCR) level is a robust predictor of cf-mtDNA and cf-nDNA in CKD patients. Baseline urine levels of cf-mtDNA and cf-nDNA could predict renal outcomes at 6 months. CONCLUSIONS: Urinary cf-mtDNA and cf-nDNA may provide novel prognostic biomarkers for renal outcome in CKD patients. The levels of plasma cf-nDNA and plasma NGAL are significantly correlated with the severity of CKD.

Development and validation of a nomogram for urothelial cancer in patients with chronic kidney disease.

Urothelial cancer (UC) is a common kidney cancer in Taiwan and patients with chronic kidney disease (CKD) are more at risk for UC than the general population. The diagnostic value of urine analysis and urine cytology is limited, especially in CKD patients. The aim of the study is to develop a nomogram to predict the risk of UC in CKD patients. We enrolled 169 UC patients and 1383 CKD patients from 9 hospitals in Taiwan between 2012 and 2015. CA125, HE4, clinical characteristics, and medical history were analyzed using multivariable logistic regression for its association with UC. A nomogram was developed to predict the risk of UC and was validated using Bootstrap. CA125 was associated with UC in CKD patients (OR: 5.91, 95% CI: 3.24-10.77) but HE4 was not (OR: 1.29, 95% CI: 0.67-2.35). A nomogram based on patients' age, estimated glomerular filtration rate, CA125 (log transformed), smoking, exposure of environmental toxin, use of nonsteroid anti-inflammatory drugs, and use of traditional Chinese medicine was conducted. The AUC of the nomogram was 0.90 (95% CI: 0.86-0.92, p < 0.01). Serum CA125 may identify UC patients from CKD patients but has limited diagnostic value due to low sensitivity. The diagnostic value of serum CA125 level can be improved by the combination with clinical characteristics including age, renal function, and medical history.

Renal chymase-dependent pathway for angiotensin II formation mediated acute kidney injury in a mouse model of aristolochic acid I-induced acute nephropathy.

Angiotensin-converting enzyme (ACE) is the primary enzyme that converts angiotensin I (Ang I) to angiotensin II (Ang II) in the renin-angiotensin system (RAS). However, chymase hydrates Ang I to Ang II independently of ACE in some kidney diseases, and it may play an important role. The present study investigated whether chymase played a crucial role in aristolochic acid I (AAI)-induced nephropathy. C57BL/6 mice were treated with AAI via intraperitoneal injection for an accumulated AAI dosage of 45 mg/kg body weight (BW) (15 mg/kg BW per day for 3 days). The animals were sacrificed after acute kidney injury development, and blood, urine and kidneys were harvested for biochemical and molecular assays. Mice exhibited increased serum creatinine, BUN and urinary protein after the AAI challenge. Significant infiltrating inflammatory cells and tubular atrophy were observed in the kidneys, and high immunocytokine levels were detected. Renal RAS-related enzyme activities were measured, and a significantly increased chymase activity and slightly decreased ACE activity were observed in the AAI-treated mice. The renal Ang II level reflected the altered profile of RAS enzymes and was significantly increased in AAI-treated mice. Treatment of AAI-induced nephropathic mice with an ACE inhibitor (ACEI) or chymase inhibitor (CI; chymostatin) reduced renal Ang II levels. The combination of ACEI and CI (ACEI+CI) treatment significantly reversed the AAI-induced changes of Ang II levels and kidney inflammation and injuries. AAI treatment significantly increased renal p-MEK without increasing p-STAT3 and p-Smad3 levels, and p-MEK/p-ERK1/2 signalling pathway was significantly activated. CI and ACEI+CI treatments reduced this AAI-activated signaling pathway. AAI-induced nephropathy progression was significantly mitigated with CI and ACEI+CI treatment. This study elucidates the role of RAS in the pathogenesis of AAI-induced nephropathy.

High particulate matter 2.5 levels and ambient temperature are associated with acute lung edema in patients with nondialysis Stage 5 chronic kidney disease.

BACKGROUND: Numerous studies have shown that exposure to air pollution, especially particulate matter (PM) with a diameter <2.5 µm (PM2.5), was associated with various diseases. We tried to determine the impact of PM2.5 and other weather factors on acute lung edema in patients with Stage 5 nondialysis chronic kidney disease (CKD Stage 5-ND). METHODS: In total, 317 CKD Stage 5-ND (estimated glomerular filtration rate 6.79 ± 4.56 mL/min) patients residing in central Taiwan who developed acute lung edema and initiated long-term dialysis were included in this case-crossover study. Pearson's correlation test was used to examine the relationship of acute lung edema cases with PM2.5 levels and ambient temperature separately. RESULTS: The average PM2.5 level within the 7-day period correlated with acute lung edema incidence in the fall [adjusted odds ratio (OR) 3.23, P = 0.047] and winter (adjusted OR 1.99, P < 0.001). In winter, even a 3-day exposure to PM2.5 was associated with increased risk (adjusted OR 1.55, P < 0.001). The average temperatures within 3 days in spring and summer were correlated positively with the risk (adjusted OR 2.77 P < 0.001 and adjusted OR 2.72, P < 0.001, respectively). In the fall and winter, temperatures were correlated negatively with the risk (adjusted OR 0.36, P < 0.001 and adjusted OR 0.54, P < 0.001, respectively). CONCLUSIONS: A high PM2.5 level was associated with an increased risk of acute lung edema. High ambient temperature in hot seasons and low ambient temperature in cold seasons were also associated with increased risk. It is essential to educate these patients to avoid areas with severe air pollution and extreme ambient temperature.

Favourable renal outcomes after intravenous thrombolytic therapy for acute ischemic stroke: Clinical implication of kidney-brain axis.

AIM: Recombinant tissue plasminogen activator (rt-PA) administration is the most prevalent treatment for acute ischemic within golden time. However, the effects of rt-PA on the kidney function in such patients remain unknown. This study determined long-term renal outcomes in patients with acute ischemic stroke receiving systemic rt-PA. METHODS: We enroled patients who were hospitalized for acute ischemic stroke from January 2001 to January 2017. We applied 1:2 propensity score matching to eliminate various confounding variables. We defined surrogate renal outcomes as declining of estimated glomerular filtration rate (eGFR) greater than 30% and 50%, and chronic kidney disease (CKD) with eGFR less than 60 mL/min. We then compared the 1-year eGFR with paired t-test in patients treated with or without rt-PA. RESULTS: Overall, 343 of 1739 patients received rt-PA within golden time. After 1:2 propensity score matching, their baseline characteristics were grouped as treated with rt-PA (n = 235) or not (n = 394). rt-PA-treated patients exhibited slower renal progression, including the risk of eGFR declining greater than 30% (hazard ratio (HR), 0.72; P = 0.03), risk of declining eGFR greater than 50% (HR, 0.63; P = 0.046) and risk of CKD (HR, 0.61; P = 0.005). After 1-year cohort, the rt-PA group exhibited an improved renal outcome by the paired t-test (propensity match: ΔGFR = 9.1 (95% confidence interval: 6.3, 11.8), P < 0.001 in rt-PA group; ΔGFR = -1.1 (95% confidence interval: -2.9, 0.7), P = 0.23 in non-rt-PA group). In patients with eGFR less than 45 mL/min (n = 34), intracerebral haemorrhage was not reported. CONCLUSION: Patients receiving rt-PA for acute ischemic stroke exhibit favourable renal outcomes, and no increased incidence of intracerebral haemorrhage occurs in rt-PA patients with advanced CKD.

Cyclophilin A and CD147 associate with progression of diabetic nephropathy.

To find the associations of circulating cyclophilin A (CyP A) and CD147/EMMPRIN with renal outcomes in type 2 diabetes patients and possible pathogenesis involved. Total 131 patients were recruited since 2004. Glycated hemoglobin, blood glucose and urine albumin-creatinine ratio levels at baseline and every 3 months were measured. Plasma CyP A and CD147 were also measured at baseline. Patients were divided into two groups based upon the median level of the baseline plasma CyP A value: < 93.64 ng/mL (group A, n = 65), ≥ 93.64 ng/mL (group B, n = 66). The estimated glomerular filtration rate was calculated at each follow-up visit. Besides, mitochondrial function assay by cellular mitochondrial energy utility was studied when cells were exposed to glucose or exogenous CyP A or both. Multivariate analysis, using median level (93.64) ng/mL as the cut-off value, revealed that circulating CyP A and CD147 levels at baseline were associated with the baseline estimated glomerular filtration rate (eGFR) (p = .042 and p = .001 separately) in cross-sectional analysis. Longitudinally, higher baseline plasma CyP A level was also correlated to a rapid decline in eGFR (p = .016). The results were also significant when using the continuous plasma CyP A level (p = .003). In cells exposed to glucose, results of oxygen consumption rate (OCR) showed a significant reduction in basal respiration, maximal respiration and ATP production. Depressed OCR further occurred when incubated with both of CyP A and glucose. Plasma CyP A and CD147 can serve as indicators of renal disease progression in type 2 diabetes patients.