Transcriptome landscape reveals the chronic inflammatory response in kidneys affected by the combinatory effect of leptospirosis and nephrotoxic injury.

Leptospirosis can cause chronic kidney damage, putting patients at risk of additional kidney injury due to other factors that can lead to renal failure. To understand the combined effect, the transcriptome profiles of kidneys of mice with adenine-induced and chronically Leptospira-infected kidneys were analysed. Chronic inflammation and T-helper 17 immune responses were activated and a high-level expression of Indoleamine 2,3-dioxygenase 1 protein was found. The results indicate that the combination may predispose patients to chronic inflammation, kidney function disruption, and symptoms seen in progressive chronic kidney disease (CKD). Furthermore, immunometabolic regulation may contribute to renal injury caused by chronic leptospirosis with secondary nephrotoxic injury. This study identified several significantly disrupted genes that could serve as potential targets for the diagnosis or treatment of CKD. Our work provides insight into the combined effect of leptospirosis and secondary kidney damage and the molecular basis for rapid progression of CKD.

Characteristics of acute ischemic stroke in patients with Nephrotic syndrome.

The incidence of ischemic stroke (IS) is higher in nephrotic syndrome (NS) patients compared to general population. However, there is limited information on the specific characteristics to stroke patients with NS. In this study, we aimed to examine the clinical manifestations of acute IS in a large group of NS patients, comparing to those without NS. We conducted a retrospective cohort study to compare the clinical presentations of acute IS in patients with and without NS. This study was a multi-institutional study and used data from Chang Gung Research Database of Taiwan from 1 January 2001, to 31 December 2017. A total of 233 IS patients with NS and 1358 IS patients without NS were enrolled. The median age of participants was 68 (range: 59-79) years. The risk of dependent functional status (modified Rankin Scale score≧3) after IS was higher in NS patients compared to those without NS (Odd ratio (OR) 4.02, 95% confidence interval (CI) 2.39 to 6.76, p < 0.001), particularly in stroke subtypes as small-artery occlusion (OR 8.02, 95% CI 3.94 to 16.32, p < 0.001), and stroke of undetermined etiology (OR 2.47, CI 1.06 to 5.76, p = 037). The risks of mortality or stroke recurrence within 30 days were similar between the two groups for all stroke subtypes. In conclusion, NS was associated with a higher risk of functional dependence following IS. Intensive treatment and rehabilitation should be considered for IS patients with NS.

Hospitalization in patients with dialysis in Taiwan: A nationwide population-based observational study.

BACKGROUND: The hospitalization rate is higher in patients with end-stage kidney disease (ESKD) than in the general population. However, the national estimates in Taiwan remain unclear. Therefore, we investigated the hospitalization rates of ESKD patients in a disease-specific manner from 2010 to 2018 in Taiwan. METHODS: This population-based study was conducted using data from the National Health Insurance Research Database. We analyzed the hospitalization rates of patients with ESKD, defined as continuous dialysis for at least three successive months. The first diagnosis at discharge for each hospitalization was defined as the main diagnosis of hospitalization. The hospitalization rate in a certain year was calculated as the number of hospitalizations divided by the number of patients undergoing chronic dialysis in the respective year. RESULTS: Hospitalization occurred in half of all prevalent ESKD patients, with an increasing trend over time. The hospitalization rate increased from 964.1 per 1000 person-years in 2010 to 1037.9 per 1000 person-years in 2018. ESKD patients who were male, aged over 75 years, and receiving hemodialysis had higher hospitalization rates. Infection-related hospitalization was the main cause of hospitalization, followed by cardiovascular disease. The 30-day re-admission rate was 19%, and the in-hospital mortality rate was 9%. CONCLUSION: Hospitalization rates continued to increase from 2010 to 2018. The high hospitalization rates for infection-related diseases and hemodialysis patients call for further strategies to be developed that reduce the hospitalization burden.

Exosomal microRNAs miR-30d-5p and miR-126a-5p Are Associated with Heart Failure with Preserved Ejection Fraction in STZ-Induced Type 1 Diabetic Rats.

Exosomal microRNAs (EXO-miRNAs) are promising non-invasive diagnostic biomarkers for cardiovascular disease. Heart failure with preserved ejection fraction (HFpEF) is a poorly understood cardiovascular complication of diabetes mellitus (DM). Little is known about whether EXO-miRNAs can be used as biomarkers for HFpEF in DM. We aimed to investigate the relationship between EXO-miRNAs and HFpEF in STZ-induced diabetic rats. We prepared STZ-induced diabetic rats exhibiting a type 1 DM phenotype with low body weight, hyperglycemia, hyperlipidemia and hypoinsulinemia. Histological sections confirmed atrophy and fibrosis of the heart, with collagen accumulation representing diabetic cardiomyopathy. Significant decreases in end-diastolic volume, stroke volume, stroke work, end-systolic elastance and cardiac output indicated impaired cardiac contractility, as well as mRNA conversion of two isoforms of myosin heavy chain (α-MHC and ß-MHC) and increased atrial natriuretic factor (ANF) mRNA indicating heart failure, were consistent with the features of HFpEF. In diabetic HFpEF rats, we examined a selected panel of 12 circulating miRNAs associated with HF (miR-1-3p, miR-21-5p, miR-29a-5p, miR-30d-5p, miR-34a-5p, miR-126a-5p, miR-143-3p, miR-145-5p, miR-195-5p, miR-206-3p, miR-320-3p and miR-378-3p). Although they were all expressed at significantly lower levels in the heart compared to non-diabetic controls, only six miRNAs (miR-21-5p, miR-30d-5p, miR-126a-5p, miR-206-3p, miR-320-3p and miR-378-3p) were also reduced in exosomal content, while one miRNA (miR-34a-5p) was upregulated. Similarly, although all miRNAs were correlated with reduced cardiac output as a measure of cardiovascular performance, only three miRNAs (miR-30d-5p, miR-126a-5p and miR-378-3p) were correlated in exosomal content. We found that miR-30d-5p and miR-126a-5p remained consistently correlated with significant reductions in exosomal expression, cardiac expression and cardiac output. Our findings support their release from the heart and association with diabetic HFpEF. We propose that these two EXO-miRNAs may be important for the development of diagnostic tools for diabetic HFpEF.

Characteristics of ischemic stroke and intracranial hemorrhage in patients with nephrotic syndrome.

BACKGROUND: The incidence of cerebral stroke, including ischemic infarction and intracranial hemorrhage (ICH), increases in patients with nephrotic syndrome (NS). However, the clinical characteristics of patients with NS and stroke remain elusive. We aimed to investigate the clinical presentation and prognosis among patients with NS and ischemic stroke (IS) or ICH. METHODS: We conducted a population-based retrospective cohort study of patients with NS and acute stroke using the Chang Gung Research Database of Taiwan from January 1, 2001, to December 31, 2017. The participants were recruited from the 7 branches of Chang Gung Memorial Hospital. RESULTS: A total of 233 patients with IS and 57 patients with ICH were enrolled. The median age was 60 (52-70) years. The prevalence rates of hyperlipidemia, hyperuricemia, and smoking were higher in IS than in ICH. IS demonstrated lower white blood cell count (7.80 vs. 8.92 × 109/L) and high-sensitivity C-reactive protein level (33.42 vs. 144.10 nmol/L) and higher cholesterol (5.74 vs. 4.84 mmol/L), triglyceride (1.60 vs. 1.28 mmol/L), and albumin (24 vs. 18 g/L) levels compared with ICH. The dependent functional status and 30-day mortality were higher in ICH than in IS. The risk factors for 30-day mortality for patients with NS and stroke were coronary artery disease (CAD), ICH, and total anterior circulation syndrome. The multivariate Cox regression analysis revealed that CAD was positively associated with 30-day mortality in patients with IS (hazard ratio 24.58, 95 % CI 1.48 to 408.90). In patients with ICH, CAD and subarachnoid hemorrhage were positively associated with 30-day mortality (hazard ratio 5.49, 95 % CI 1.54 to 19.56; hazard ratio 6.32, 95 % CI 1.57 to 25.53, respectively). CONCLUSIONS: ICH demonstrated a higher risk of dependence and 30-day mortality compared with IS in patients with NS. Intensive monitoring and treatment should be applied particularly in patients with NS and ICH.

A Novel Murine Model Expressing a Chimeric mSCARB2/hSCARB2 Receptor Is Highly Susceptible to Oral Infection with Clinical Isolates of Enterovirus 71.

Enterovirus 71 (EV71) infection is generally associated with hand-foot-and-mouth disease (HFMD) and may cause severe neurological disorders and even death. An effective murine oral infection model for studying the pathogenesis of various clinical EV71 isolates is lacking. We developed a transgenic (Tg) mouse that expresses an EV71 receptor, that is, human scavenger receptor class B member 2 (hSCARB2), in a pattern highly similar to that of endogenous murine SCARB2 (mSCARB2) protein. A FLAG-tagged SCARB2 cDNA fragment composed of exons 3 to 12 was inserted into a murine Scarb2 gene-containing bacterial artificial chromosome (BAC) clone, and the resulting transgene was used for establishment of chimeric receptor-expressing Tg mice. Tg mice intragastrically (i.g.) infected with clinical isolates of EV71 showed neurological symptoms, such as ataxia and paralysis, and fatality. There was an age-dependent decrease in susceptibility to viral infection. Pathological characteristics of the infected Tg mice resembled those of encephalomyelitis in human patients. Viral infection was accompanied by microglial activation. Clodronate treatment of the brain slices from Tg mice enhanced viral replication, while lipopolysaccharide treatment significantly inhibited it, suggesting an antiviral role for microglia during EV71 infection. Taken together, this Tg mouse provides a model that closely mimics natural infection for studying EV71 pathogenesis and for evaluating the efficacy of vaccines or other antiviral drugs.IMPORTANCE The availability of a murine model of EV71 infection is beneficial for the understanding of pathogenic mechanisms and the development and assessment of vaccines and antiviral drugs. However, the lack of a murine oral infection model thwarted the study of pathogenesis induced by clinically relevant EV71 strains that are transmitted via the oral-oral or oral-fecal route. Our Tg mice could be intragastrically infected with clinically relevant EV71 strains in an efficient way and developed neurological symptoms and pathological changes strikingly resembling those of human infection. Moreover, these mice showed an age-dependent change in susceptibility that is similar to the human case. This Tg mouse, when combined with the use of other genetically modified mice, potentially contributes to studying the relationship between developmental changes in immunity and susceptibility to virus.

Therapeutic potential of cPLA2 inhibitor to counteract dilated-cardiomyopathy in cholesterol-treated H9C2 cardiomyocyte and MUNO rat.

BACKGROUND AND PURPOSE: The pathogenesis of cardiomyopathy in metabolically unhealthy obesity (MUO) has been well studied. However, the pathogenesis of cardiomyopathy typically associated with high cholesterol levels in metabolically unhealthy nonobesity (MUNO) remains unclear. We investigated whether cholesterol-generated LysoPCs contribute to cardiomyopathy and the role of cytosolic phospholipase A2 (cPLA2) inhibitor in cholesterol-induced MUNO. EXPERIMENTAL APPROACH: Cholesterol diet was performed in Sprague-Dawley rats that were fed either regular chow (C), or high cholesterol chow (HC), or HC diet with 10 % fructose in drinking water (HCF) for 12 weeks. LysoPCs levels were subsequently measured in rats and in MUNO human patients. The effects of cholesterol-mediated LysoPCs on cardiac injury, and the action of cPLA2 inhibitor, AACOCF3, were further assessed in H9C2 cardiomyocytes. KEY RESULTS: HC and HCF rats fed cholesterol diets demonstrated a MUNO-phenotype and cholesterol-induced dilated cardiomyopathy (DCM). Upregulated levels of LysoPCs were found in rat myocardium and the plasma in MUNO human patients. Further testing in H9C2 cardiomyocytes revealed that cholesterol-induced atrophy and death of cardiomyocytes was due to mitochondrial dysfunction and conditions favoring DCM (i.e. reduced mRNA expression of ANF, BNP, DSP, and atrogin-1), and that AACOCF3 counteracted the cholesterol-induced DCM phenotype. CONCLUSION AND IMPLICATIONS: Cholesterol-induced MUNO-DCM phenotype was counteracted by cPLA2 inhibitor, which is potentially useful for the treatment of LysoPCs-associated DCM in MUNO.

Administration of low-dose resveratrol attenuated hepatic inflammation and lipid accumulation in high cholesterol-fructose diet-induced rat model of nonalcoholic fatty liver disease.

Resveratrol (RSV) has been demonstrated to ameliorate nonalcoholic fatty liver disease (NAFLD) in animal studies. However, RSV was given with the dosage that ranged from 7 to 300 mg/kg body weight (BW). Hence, the study aimed to investigate the efficacy of RSV at a lower dosage on high cholesterol-fructose diet (HCFD)-induced rat model of NAFLD. In the study, male Sprague-Dawley rats were fed with HCFD for 15 weeks. RSV was also given at a daily dose of 1 mg/kg BW for 15 days or 15 weeks by oral delivery. At sacrifice, plasma and liver specimens were acquired for detections of alanine and aspartate aminotransferases, proinflammatory cytokines, and lipid contents. Histological examinations and Western blotting analysis were performed using liver tissues. The results showed that RSV administration reduced plasma levels of aminotransferases and proinflammatory cytokines including interleukin-1 beta (IL-1ß), IL-6, and tumor necrosis factor-alpha (TNF-α) in HCFD-induced NAFLD. RSV also mitigated hepatic lipid accumulation and expression of IL-1ß, IL-6, and TNF-α. Besides, phosphorylation of signal transducer and activator of transcription 3 (STAT3) was reduced with RSV supplementation in the liver of HCFD-fed rats. We concluded that low-dose RSV supplementation attenuated hepatic inflammation and lipid accumulation in HCFD-induced NAFLD. The ameliorative effect of RSV on NAFLD could be associated with downregulation of phosphorylated STAT3.

Resveratrol Mitigates High-Fat Diet-Induced Vascular Dysfunction by Activating the Akt/eNOS/NO and Sirt1/ER Pathway.

We investigated whether resveratrol (RSV) can attenuate obesity and diabetes progression and improve diabetes-induced vascular dysfunction, and we attempted to delineate its underlying mechanisms. Male C57Bl/6 mice were administered a high-fat diet (HFD) for 17 weeks. Mice developed type 2 diabetes with increased body weight, hyperglycemia, hyperinsulinemia, and hyperlipidemia. Oral gavage with RSV significantly reversed the symptoms induced by the HFD. Insulin sensitivity likewise improved after the RSV intervention in these mice. Phenylephrine-induced cremaster arteriolar constriction was impaired, whereas RSV treatment significantly mitigated the vessel responsiveness to phenylephrine. The obese diabetic mice exhibited increased leukocyte rolling, adhesion, and transmigration in the postcapillary venules of the cremaster muscle. By contrast, RSV treatment significantly attenuated HFD-induced extravasation. RSV significantly recovered phosphorylated Akt and eNOS expression in the thoracic aorta. In addition, activated adenosine monophosphate-activated protein kinase in the thoracic aorta was involved in the improvement of epithelial function after RSV intervention. RSV considerably upregulated the plasma NO level in HFD mice. Moreover, RSV-enhanced human umbilical vein endothelial cells healing through Sirt1/ER pathway may be involved in the prevention of leukocyte extravasation. Collectively, RSV attenuates diabetes-induced vascular dysfunction by activating Akt/eNOS/NO and Sirt1/ER pathway. Our mechanistic study provides a potential RSV-based therapeutic strategy against cardiovascular disease.

Dietary Leucine Supplement Ameliorates Hepatic Steatosis and Diabetic Nephropathy in db/db Mice.

Dietary leucine supplementation has been explored for the therapeutic intervention of obesity and obesity-induced metabolic dysfunctions. In this study, we aim to examine the effects of dietary leucine supplementation in db/db mice. Mice were treated with or without leucine (1.5% w/v) in drinking water for 12 weeks. The leucine supplement was found to reduce insulin resistance and hepatic steatosis in db/db mice. Using Nuclear Magnetic Resonance (NMR)-based lipidomics, we found that the reduction of hepatic triglyceride synthesis was correlated with attenuated development of fatty liver. In addition, diabetic nephropathy (DN) was also ameliorated by leucine. Using liquid chromatography⁻time-of-flight mass spectrometry (LC-TOF MS)-based urine metabolomics analysis, we found that the disturbance of the tricarboxylic acid (TCA) cycle was reversed by leucine. The beneficial effects of leucine were probably due to AMP-activated protein kinase (AMPK) activation in the liver and kidneys of db/db mice. Thus, dietary leucine supplementation may potentially be a nutritional intervention to attenuate hepatic steatosis and early DN in type II diabetes.

Association between blood cadmium levels and malnutrition in peritoneal dialysis.

BACKGROUND: Malnutrition is associated with an increased risk of cardiovascular death and may cause protein-energy wasting in individuals with chronic kidney disease. A previous study demonstrated that blood cadmium levels (BCLs) were associated with malnutrition in maintenance hemodialysis (MHD) patients. However, the correlation between cadmium exposure and malnutrition remains unclear in chronic peritoneal dialysis (CPD) patients. This study examined the possible adverse effects of environmental cadmium exposure in CPD patients. METHODS: A total of 301 CPD patients were enrolled and divided into 3 study groups based on the following BCL tertiles: low (<0.19 µg/L), middle (0.19-0.39 µg/L), and high (>0.39 µg/L). Demographic, hematological, biochemical, and dialysis-related data were obtained for analysis. The analysis also included values of nutritional and inflammatory markers. RESULTS: The BCLs of CPD patients were lower than those of MHD patients. At baseline, patients in the high BCL group were older and had a higher prevalence of diabetes mellitus but lower serum albumin, creatinine, and phosphate levels than the patients in the other 2 groups. After adjusting for potential variables, stepwise backward multiple linear regression analysis revealed that age and alanine aminotransferase levels were positively associated with logarithmic transformation of BCLs (log BCLs), while serum albumin levels were negatively associated with log BCLs in CPD patients. The log BCLs were a significant determinant (beta coefficient ± standard error = -0.185 ± 0.074; P = 0.013) of nutritional status and significantly associated with the presence of malnutrition (odds ratio = 2.64; 95% confidence interval: 1.07-6.48; P = 0.035) in CPD patients after adjustment for related variables. CONCLUSIONS: BCL is significantly associated with nutritional status and malnutrition in CPD patients. Therefore, it is important for CPD patients to avoid environmental exposure to cadmium such as through smoking and consumption of cadmium-rich foods.

Baseline hyponatremia does not predict two-year mortality in patients with chronic peritoneal dialysis.

PURPOSE: Hyponatremia is a common electrolyte abnormality in a variety of medical conditions. Lower predialysis serum sodium concentration is associated with an increased risk of death in oligoanuric patients on hemodialysis. However, whether hyponatremia affects the short-term mortality in chronic peritoneal dialysis (CPD) patients remains unclear. METHODS: We conducted a cross-sectional and two-year follow-up review retrospectively, and 318 patients with CPD were enrolled in a medical center. Serum sodium levels were measured at baseline and categorized as quartile of Na: quartile 1 (124-135 mEq/L), quartile 2 (136-139), quartile 3 (140-141) and quartile 4 (142-148). Mortality and cause of death were recorded for longitudinal analyses. RESULTS: The patients with higher quartile (higher serum sodium) had a trend of lower age, peritoneal dialysis (PD) duration, co-morbidity index, D/P Cr and white blood cell counts and higher renal Kt/Vurea (Kt/V) and serum albumin level. Stepwise multiple linear regression analysis showed that serum sodium level was positively associated with albumin, residual renal Kt/V and negatively associated with age and PD duration in CPD patients. After two-year follow-up, stepwise multivariate Cox proportional hazards model demonstrated that age, co-morbidity index and serum albumin were the significant risk factors for all-cause two-year mortality, but not serum sodium levels. CONCLUSIONS: Serum sodium level in CPD patients is associated with nutritional status, residual renal function and duration of PD. However, baseline serum sodium level is not an independent predictor of two-year mortality in CPD patients.

Weekly intraperitoneal steroid infusion to treat recurrent ascites in a patient with early stage of peritoneal dialysis-related encapsulating peritoneal sclerosis: A case report.

Encapsulating peritoneal sclerosis (EPS) is a rare and potentially fatal complication of long-term peritoneal dialysis (PD). EPS-induced large volume and recurrent ascites represents a challenging condition. We report a 51-year-old man with kidney failure treated with PD for 13 years who eventually developed early stage of EPS accompanied with poor intake and recurrent ascites. After management including discontinuing PD and switching to haemodialysis, as well as oral steroids and tamoxifen administration, the patient had refractory ascites. An intervention of weekly intraperitoneal steroid infusion with methylprednisolone was implemented for a year. Gradually, we observed a reduction in ascites drainage, an improvement of clinical symptoms and the patient's nutritional status. The PD catheter was successfully removed as there was no recurrence of ascites. Intraperitoneal corticosteroid administration represents a new intervention for patients with early stage of EPS and recurrent ascites after PD cessation.

Long-term renal function alterations in hepatitis C patients with SVRs: Impacts of therapies and mixed cryoglobulinemia.

BACKGROUND / AIMS: Effects of anti-hepatitis C virus (HCV) therapeutic regimens and mixed cryoglobulinemia on long-term renal function of HCV-infected patients with viral clearance have not been determined. METHODS/MATERIALS: A prospective 10-year cohort study of 1212 HCV-infected patients (interferon-based therapy, n = 615; direct-acting antiviral (DAA) therapy, n = 434) was conducted. RESULTS: At baseline, age, body mass index (BMI), hemoglobin (Hb) and uric acid (UA) levels, and fibrosis-4 score were associated with estimated glomerular filtration rates (eGFRs) in HCV-infected patients. At 24 weeks posttherapy, age, BMI, and Hb and UA levels were associated with eGFRs in patients with a sustained virological response (SVR) (n = 930). Compared with those at baseline, the eGFRs were lower in SVR patients at 24 weeks posttherapy, regardless of the therapeutic regimen. The eGFRs reverted to baseline levels in interferon-treated SVR patients up to 10 years posttherapy but remained decreased in DAA-treated SVR patients up to 4 years posttherapy. Longitudinally, repeated measures analyses with generalized estimating equations showed that the interactions between DAA-based therapy and mixed cryoglobulinemia (OR: 3.291) and Hb levels (1.778) were positively, while DAA-based therapy (0.442), age (0.956), UA levels (0.698), homeostasis model assessment-insulin resistance index (0.961) and complement 4 levels (0.9395) were negatively associated with the eGFR. Among DAA-treated SVR patients, the baseline eGFR (OR: 1.014; 95%CI OR: 1.004-1.023) and high-sensitivity C-reactive protein (HR: 1.082; 95%CI HR: 1.018-1.15) were associated with eGFR reduction at 24 weeks and 4 years posttherapy, respectively. CONCLUSIONS: Hepatic fibrosis was an HCV-related factor for renal function. Longitudinally, DAA therapy was negatively, while the interaction between DAA therapy and mixed cryoglobulinemia was positively associated with renal function in SVR patients; deteriorated renal function was recovered in interferon-treated SVR patients. Particularly in DAA-treated SVR patients, baseline renal function and systemic inflammation were associated with short- and long-term reductions in renal function, respectively.

Neurodegeneration in streptozotocin-induced diabetic rats is attenuated by treatment with resveratrol.

AIM: Diabetes mellitus-associated hyperglycemia and oxidative stress have been shown to have detrimental effects on the brain and may lead to impairment of cognitive functions. Resveratrol (Rsv), a polyphenolic antioxidant, has been shown to have moderate hypoglycemic and prominent hypolipidemic effects in diabetic rats. In the present study, we examined if Rsv improves the diabetic encephalopathy and explored its possible underlying mechanisms. METHODS: Male SD rats were treated with streptozotocin (65 mg/kg), and the diabetic rats were orally fed with Rsv (0.75 mg/kg, every 8 h) or normal saline for 4 weeks. Animals were then sacrificed and the brain tissues (hippocampus) processed for biochemical and histological studies. RESULTS: Neurodegeneration and astrocytic activation were noted in the hippocampus of the diabetic rats. Tumor necrosis factor-α, IL-6 transcripts and nuclear factor-κB expression were increased in the brain. In addition, neuropathic alterations in the hippocampus were evident in diabetic rats, including increased blood vessel permeability and VEGF expression, decreased mitochondrial number and AMP-activated protein kinase activity. In Rsv-treated diabetic rats, the aforementioned abnormalities were all attenuated. CONCLUSION: These observations suggest that Rsv significantly attenuated neurodegeneration and astrocytic activation in the hippocampus of diabetic rats. Our results suggested that Rsv could potentially be a new therapeutic agent for diabetic encephalopathy and neurodegeneration.

Education level is associated with mortality in male patients undergoing maintenance hemodialysis.

BACKGROUND: Studies of the correlation between education levels and mortality in hemodialysis (HD) patients are rare. The aim of this multi-center study was to investigate the relationship between education levels and 3-year mortality rates in HD patients. METHODS: A total of 935 HD patients from 3 HD centers participated in this 3-year prospective observational study. Education levels were categorized as either less than senior high school and above or equal to senior high school. The causes of death and mortality rates were also analyzed for each subgroup. RESULTS: At the end of the 3-year follow-up period, 164 patients had died. In the male group, forward stepwise Cox regression analysis revealed that age, HD duration, hypertension, creatinine level, serum albumin level ≥3.6 g/dl, anuria, Kt/Vurea, and high education level were significant predictive factors for 3-year mortality rates. CONCLUSION: This prospective observational study demonstrated that education level was associated with mortality in men undergoing HD.

Effect of sodium bicarbonate on cardiovascular outcome and mortality in patients with advanced chronic kidney disease.

Background: Metabolic acidosis is a common complication in patients with chronic kidney disease (CKD). Oral sodium bicarbonate is often used to treat metabolic acidosis and prevent CKD progression. However, there is limited information about the effect of sodium bicarbonate on major adverse cardiovascular events (MACE) and mortality in patients with pre-dialysis advanced CKD. Method: 25599 patients with CKD stage V between January 1, 2001 and December 31, 2019 were identified from the Chang Gung Research Database (CGRD), a multi-institutional electronic medical record database in Taiwan. The exposure was defined as receiving sodium bicarbonate or not. Baseline characteristics were balanced using propensity score weighting between two groups. Primary outcomes were dialysis initiation, all-cause mortality, and major adverse cardiovascular events (MACE) (myocardial infarction, heart failure, stroke). The risks of dialysis, MACE, and mortality were compared between two groups using Cox proportional hazards models. In addition, we performed analyzes using Fine and Gray sub-distribution hazard models that considered death as a competing risk. Result: Among 25599 patients with CKD stage V, 5084 patients (19.9%) were sodium bicarbonate users while 20515 (80.1%) were sodium bicarbonate non-users. The groups had similar risk of dialysis initiation (hazard ratio (HR): 0.98, 95% confidence interval (CI): 0.95-1.02, p < 0.379). However, taking sodium bicarbonate was associated with a significantly lower risks of MACE (HR: 0.95, 95% CI 0.92-0.98, p < 0.001) and hospitalizations for acute pulmonary edema (HR: 0.92, 95% CI 0.88-0.96, p < 0.001) compared with non-users. The mortality risks were significantly lower in sodium bicarbonate users compared with sodium bicarbonate non-users (HR: 0.75, 95% CI 0.74-0.77, p < 0.001). Conclusion: This cohort study revealed that in real world practice, use of sodium bicarbonate was associated with similar risk of dialysis compared with non-users among patients with advanced CKD stage V. Nonetheless, use of sodium bicarbonate was associated with significantly lower rate of MACE and mortality. Findings reinforce the benefits of sodium bicarbonate therapy in the expanding CKD population. Further prospective studies are needed to confirm these findings.

Effect of chelation therapy on progressive diabetic nephropathy in patients with type 2 diabetes and high-normal body lead burdens.

BACKGROUND: A previous study in type 2 diabetic patients with high-normal body lead burdens showed that EDTA chelation therapy for 3 months slows progressive diabetic nephropathy during a 12-month follow-up. The effect of a longer course of therapy on kidney function decrease over a longer follow-up is not known. STUDY DESIGN: A 12-month run-in phase, then a randomized single-blind study with a 27-month intervention. SETTING & PARTICIPANTS: University medical center; 50 patients (serum creatinine, 1.5-3.9 mg/dL) with high-normal body lead burden (≥80-<600 µg) were randomly assigned to the treatment and control groups. INTERVENTION: The treatment group received weekly chelation therapy for 3 months to reduce their body lead burden to <60 µg and then as needed for 24 months to maintain this level. The control group received placebo for 3 months and then weekly for 5 weeks at 6-month intervals for 24 months. OUTCOMES: The primary end point was change in estimated glomerular filtration rate (eGFR) over time. A secondary end point was a 2-fold increase in baseline serum creatinine level or the requirement for renal replacement therapy. MEASUREMENTS: Body lead burdens were assessed by EDTA mobilization tests and eGFR was calculated using the equation for Chinese patients with type 2 diabetes. RESULTS: Mean baseline eGFRs in the treatment and control groups were similar. After 3 months of chelation therapy, the change in eGFR in the treatment group (+1.0 ± 4.8 mL/min/1.73 m(2)) differed significantly from that in the control group (-1.5 ± 4.8 mL/min/1.73 m(2); P = 0.04). In the subsequent 24-month intervention, the yearly rate of decrease in eGFR (5.6 ± 5.0 mL/min/1.73 m(2) per year) in the treatment group was slower than that (9.2 ± 3.6 mL/min/1.73 m(2) per year; P = 0.04) in the control group. 17 (68%) control-group patients and 9 (36%) treatment-group patients achieved the secondary end point. LIMITATIONS: Small sample size, not double blind. CONCLUSIONS: A 27-month course of EDTA chelation therapy retards the progression of diabetic nephropathy in type 2 diabetic patients with high-normal body lead burdens.

Association of hyponatremia in acute stroke stage with three-year mortality in patients with first-ever ischemic stroke.

BACKGROUND: Hyponatremia is the most common electrolyte disorder in hospitalized patients, and is frequently a marker of a significant underlying disease. The prognostic value of hyponatremia in patients with acute first-ever ischemic stroke is not known. We aimed to analyze whether hyponatremia in the acute stroke stage contributed to the risk of mortality or recurrent stroke in these patients. METHODS: We studied 925 patients presenting with acute first-ever ischemic stroke between 2002 and 2004. Sodium levels were obtained on arrival at the emergency room within 3 days of acute stroke onset. Hyponatremia was defined as a serum sodium concentration of 134 mmol/l or less. Clinical presentation, stroke risk factors, associated medical disease, and outcome were recorded. All patients were followed for 3 years for survival analysis. A multivariate Cox proportional hazards model was used to identify risk factors for 3-year mortality in these patients. We also constructed Kaplan-Meier survival curves, and compared groups with hyponatremia and normonatremia by means of log rank tests for significant differences. RESULTS: Among the patients with acute first-ever ischemic stroke, 107 (11.6%) were hyponatremic. Among stroke risk factors, the prevalence of diabetes mellitus was significantly higher among hyponatremic patients (p < 0.001). Prevalence of chronic renal insufficiency was also higher in the hyponatremic group (p = 0.002). Clinical presentations, such as the length of acute ward stay, initial impaired consciousness, and clinical course in acute stroke were similar among normo- and hyponatremic patients. Among the complications, pneumonia and urinary tract infection were significantly higher in hyponatremic than in normonatremic patients. After multivariate logistic regression analysis, diabetes mellitus and chronic renal insufficiency were associated with hyponatremia in these patients. Kaplan-Meier analysis indicated that the survival rate was significantly lower in hyponatremic patients than in normonatremic patients (log rank test; p value <0.001). After multivariate Cox proportional hazards model analysis, hyponatremia was a significant predictor of 3-year mortality in these patients after adjustment for related variables (p value = 0.003, hazard ratio = 2.23, 95% confidence interval: 1.30-3.82). CONCLUSION: Hyponatremia in the acute stroke stage is a predictor of 3-year mortality in patients with acute first-ever ischemic stroke that is independent of other clinical predictors of adverse outcome.

Integrated Metabolomic and Transcriptomic Analysis of Acute Kidney Injury Caused by Leptospira Infection.

Renal leptospirosis caused by leptospiral infection is characterised by tubulointerstitial nephritis and tubular dysfunction, resulting in acute and chronic kidney injury. Metabolomic and transcriptomic data from a murine model of Leptospira infection were analysed to determine whether metabolomic data from urine were associated with transcriptome changes relevant to kidney injury caused by Leptospira infection. Our findings revealed that 37 metabolites from the urine of L. interrogans-infected mice had significantly different concentrations than L. biflexa-infected and non-infected control mice. Of these, urinary L-carnitine and acetyl-L-carnitine levels were remarkably elevated in L. interrogans-infected mice. Using an integrated pathway analysis, we found that L-carnitine and acetyl-L-carnitine were involved in metabolic pathways such as fatty acid activation, the mitochondrial L-carnitine shuttle pathway, and triacylglycerol biosynthesis that were enriched in the renal tissues of the L. interrogans-infected mice. This study highlights that L-carnitine and acetyl-L-carnitine are implicated in leptospiral infection-induced kidney injury, suggesting their potential as metabolic modulators.