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.

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.

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.

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.

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.

Statin uses in adults with non-dialysis advanced chronic kidney disease: Focus on clinical outcomes of infectious and cardiovascular diseases.

Background: Statins are commonly used for cardiovascular disease (CVD) prevention. Observational studies reported the effects on sepsis prevention and mortality improvement. Patients with chronic kidney disease (CKD) are at high risk for CVD and infectious diseases. Limited information is available for statin use in patients with non-dialysis CKD stage V. Method: The retrospective observational study included patients with non-dialysis CKD stage V, with either de novo statin use or none. Patients who were prior statin users and had prior cardiovascular events were excluded. The key outcomes were infection-related hospitalization, major adverse cardiovascular events (MACE) (non-fatal myocardial infarction, hospitalization for heart failure, or non-fatal stroke), and all-cause mortality. The data were retrieved from the Chang Gung Research Database (CGRD) from January 2001 to December 2019. Analyses were conducted with Cox proportional hazard regression models in the propensity score matching (PSM) cohort. Result: A total of 20,352 patients with CKD stage V were included (1,431 patients were defined as de novo statin users). After PSM, 1,318 statin users were compared with 1,318 statin non-users. The infection-related hospitalization (IRH) rate was 79.3 versus 94.3 per 1,000 person-years in statin users and statin non-users, respectively [hazard ratio (HR) 0.83, 95% confidence interval (CI) 0.74-0.93, p = 0.002]. The incidence of MACE was 38.9 versus 55.9 per 1,000 person-years in statin users and non-users, respectively (HR, 0.72; 95% CI 0.62-0.83, p < 0.001). The all-cause mortality did not differ between statin users and non-users, but statin users had lower infection-related mortality than non-users (HR, 0.59; 95% CI 0.38-0.92, p = 0.019). Conclusion: De novo use of statin in patients with non-dialysis CKD stage V reduced the incidence of cardiovascular events, hospitalization, and mortality for infectious disease. The study results reinforced the benefits of statin in a wide range of patients with renal impairment before maintenance dialysis.

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.

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.

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.

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.

Evolution of ferritin levels in hepatitis C patients treated with antivirals.

The evolution of ferritin levels in hepatitis C virus (HCV)-infected patients with sustained virological responses (SVRs) following various therapy regimens remains elusive. An 8-year prospective cohort study of 1194 HCV-infected patients [interferon-based therapy (n = 620), direct-acting antiviral agent (DAA) therapy (n = 355)] was conducted. At baseline, sex, alanine aminotransferase (ALT), triglycerides, homeostatic model assessment of insulin resistance (HOMA-IR), estimated glomerular filtration rate (eGFR), hemoglobin, iron/total iron-binding capacity (Fe/TIBC) and IFNL3-rs12979860 genotypes were associated with ferritin levels. At 24 weeks posttherapy, ALT, triglycerides, total cholesterol, eGFR, Fe/TIBC and the therapy regimen were associated with ferritin levels in SVR patients. Among interferon-treated patients, ferritin levels increased at 24 weeks posttherapy, regardless of SVR, and 24-week posttherapy ferritin levels were higher in non-SVR patients (n = 111) than in SVR patients (n = 509); ferritin levels began decreasing at 3 years posttherapy and were lower than pretherapy levels since 4 years posttherapy in SVR patients. Among DAA-treated SVR patients (n = 350), ferritin levels decreased and remained stable since 24 weeks posttherapy. ALT, triglycerides, eGFR, and Fe/TIBC were HCV-unrelated factors associated with ferritin levels; sex, HOMA-IR, total cholesterol, hemoglobin and IFNL3-rs12979860 genotype were HCV-related factors associated with ferritin levels. In interferon-treated SVR patients, the increased trend of posttherapy ferritin levels was not reversed until 4 years posttherapy. In DAA-treated SVR patients, ferritin levels decreased since 24 weeks posttherapy.

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.

Temporal trends of incident diabetes mellitus and subsequent outcomes in patients receiving kidney transplantation: a national cohort study in Taiwan.

BACKGROUND: Allograft kidney transplantation has become a treatment of choice for patients with end-stage renal disease (ESRD), and post-transplant diabetes mellitus (PTDM) has been associated with impaired patient and graft survival. Taiwan has the highest incidence and prevalence rates of ESRD with many recipients and candidates of kidney transplantation. However, information about the epidemiologic features of PTDM in Taiwan is incomplete. Therefore, we aimed to investigate the prevalence and incidence of PTDM with subsequent patient and graft outcomes. METHODS: Using the Taiwan National Health Insurance Research Database (NHIRD), 3663 kidney recipients between 1997 and 2011 were enrolled. We calculated the cumulative incidences of diabetes mellitus (DM) after transplantation. Cox proportional hazards model with competing risk analysis was used to calculate the hazard ratio (HR) and 95% confidence intervals (CI) between three targeted groups (DM, PTDM, non-DM). The outcomes of primary interest were the occurrence of graft failure excluding death with functioning graft, all-cause mortality, death with functioning graft and major adverse cardiovascular events (MACE) including myocardial infarction (MI), cerebrovascular accident (CVA) and congestive heart failure (CHF). Subgroup analysis for graft failure excluding death with functioning graft, MACE and all-cause mortality was performed, and interaction between PTDM and recipient age was examined. RESULTS: Of 3663 kidney transplant recipients, 531 (14%) had pre-existing DM and 631 (17%) developed PTDM. Compared with non-DM group, the PTDM and DM groups exhibited higher risk of graft failure excluding death with functioning graft (PTDM: HR 1.65, 95% CI 1.47-1.85; DM: HR 1.33, 95% CI 1.18-1.50), MACE (PTDM: HR 1.51, 95% CI 1.31-1.74; DM: HR 1.64, 95% CI 1.41-1.9), all-cause mortality (PTDM: HR 1.79, 95% CI 1.59-2.01; DM: HR 2.03, 95% CI 1.81-2.18), and death with functioning graft (PTDM: HR 1.94, 95% CI 1.71-2.20; DM: HR 1.94, 95% CI 1.71-2.21). Both PTDM and DM groups had increased cardiovascular disease-related mortality (PTDM: HR 2.14, 95% CI 1.43-3.20, p < 0.001; DM: HR 1.89, 95% CI 1.25-2.86, p = 0.002), cancer-related mortality (PTDM: HR 1.56, 95% CI 1.18-2.07, p = 0.002; DM: HR 1.89, 95% CI 1.25-2.86, p = 0.027), and infection-related mortality (PTDM: HR 1.47, 95% CI 1.14-1.90, p = 0.003; DM: HR 2.25, 95% CI 1.77-2.84, p < 0.001) compared with non-DM group. The subgroup analyses showed that the add-on risks of MACE and mortality from PTDM were mainly observed in patients who were younger and those without associated comorbidities including atrial fibrillation, cirrhosis, CHF, and MI. Age significantly modified the association between PTDM and MACE (pinteraction < 0.01) with higher risk in recipients with PTDM aged younger than 55 years (adjusted HR 1.64, 95% CI 1.40-1.92, p < 0.001). A trend (pinteraction = 0.06) of age-modifying effect on the association between PTDM and all-cause mortality was also noted with higher risk in recipients with PTDM aged younger than 55 years. CONCLUSIONS: In the present population-based study, the incidence of PTDM peaked within the first year after kidney transplantation. PTDM negatively impacted graft and patient outcomes. The magnitude of cardiovascular and survival disadvantages from PTDM were more pronounced in recipients aged less than 55 years. Further trials to improve prediction of PTDM and to prevent PTDM are warranted.

The Differences of Serum Metabolites Between Patients With Early-Stage Alzheimer's Disease and Mild Cognitive Impairment.

Background: Mild cognitive impairment (MCI) is regarded as a transition phase between normal aging and Alzheimer's disease (AD). Identification of novel and non-invasive biomarkers that can distinguish AD at an early stage from MCI is warranted for therapeutic and support planning. The goal of this study was to identify the differences of serum metabolomic profiles between MCI and early-stage AD, which could be potential non-invasive biomarkers for early diagnosis of AD. Methods: The subjects enrolled in the study were classified into two diagnostic groups: MCI (n = 40) and early-stage AD (n = 40). Targeted metabolomics analysis of serum samples was performed using the Biocrates Absolute-IDQ P180 kit. Targeted metabolic data were analyzed by TargetLynx, and MetIDQ software was applied to integrate the metabolites by automated calculation of metabolite concentrations. Results: The datasets of targeted metabolite analysis were analyzed by the orthogonal-projection-to-latent-structure-discriminant-analysis (OPLS-DA) model. The OPLS-DA score plots demonstrated considerable separation between the MCI and early-stage AD patients. The levels of pimelylcarnitine, putrescine, SM (OH) C24:1, and SM C24:0 were significantly lower, whereas the levels of acetylornithine, methionine sulfoxide, and PC ae C44:3 were significantly higher in early-stage AD patients as compared with MCI patients. Receiver operating characteristic curve analysis of a combination of three lipid metabolites [SM (OH) C24:1, SM C24:0, and PC ae C44:3] showed an acceptable discrimination between the early-stage AD and MCI patients (area under the curve = 0.788). Conclusions: Our results characterized the differences of serum metabolic profiles between MCI and early-stage AD patients. The positive findings from this study indicate that the minimally invasive method of blood sampling may help to identify patients with AD at an early stage from those with MCI.

Amino acids and wound healing in people with limb-threatening diabetic foot ulcers.

BACKGROUND: Amino acids are associated with wound healing in traumatic wounds and burns, although their effects on healing in patients with diabetic foot ulcers (DFUs) are limited. This study aimed to evaluate and identify specific amino acids associated with healing outcomes of patients with DFUs. METHODS: Sixty-two out of 85 patients who completed the in-hospital treatment for limb-threatening DFUs were enrolled. All ulcers had epithelialization without clinical evidence of infection at discharge. The patients and their families were instructed on foot-care techniques and committed to regular follow-up for 1 year. Baseline characteristics, PEDIS wound classification, laboratory data and serum amino acid levels were used to analyze their predictive power. RESULTS: Fifty-seven patients completed the study in which 38 had healed and 19 had unhealed ulcers. The unhealed group had higher incidence of coronary artery disease and larger wound size. Most patients received endovascular therapy (81.6% healed group; 78.9% unhealed group) before enrollment. Following adjustments for clinical factors, the serum levels of arginine (326.4 µmol/L vs. 245.0 µmol/L, P = 0.045), isoleucine (166.7 µmol/L vs. 130.1 µmol/L, P = 0.019), leucine (325.8 µmol/L vs. 248.9 µmol/L, P = 0.039), and threonine (186.7 µmol/L vs. 152.0 µmol/L, P = 0.019) were significantly higher in the healed group. CONCLUSIONS: The amino acids associated with wound healing in DFUs differ from those reported for traditional traumatic wounds. These findings affirm the necessity for future large-scaled studies for the application of these amino acids in DFU healing, either as prognostic predictors or supplemented regimens.

Temporal Trends of Severe Hypoglycemia and Subsequent Mortality in Patients with Advanced Diabetic Kidney Diseases Transitioning to Dialysis.

BACKGROUND: Patients with diabetic kidney disease (DKD) are at higher risk of hypoglycemia than diabetic patients without DKD. We aimed to investigate the temporal trends of severe hypoglycemia in advanced DKD patients transitioning to dialysis and examine risk factors associated with severe hypoglycemia. We also investigated the association of severe hypoglycemia episodes with one-year mortality after initiation of dialysis in patients with advanced DKD. METHODS: Using the Taiwan National Health Insurance Research Database, 46,779 advanced DKD patients transitioning to dialysis (Peritoneal dialysis 4216, hemodialysis 42,563) between 1997 and 2011 were enrolled. We calculated the rates of severe hypoglycemia from 5 years before dialysis until 10 years after dialysis. Cox proportional hazard model was used to examine the risk factors of post end stage renal disease (ESRD) one-year hypoglycemia and post ESRD one-year mortality in advanced DKD patients transitioning to dialysis. RESULTS: We found that 11.5% of advanced DKD patients had at least one episode of severe hypoglycemia the year leading up to dialysis initiation. Multivariate analysis revealed hemodialysis compared with peritoneal dialysis, stroke, use of sulfonylurea, glinide, and insulin were associated with higher risk of severe hypoglycemia one year after transitioning to dialysis. Increased frequency of severe hypoglycemia-related hospitalizations was associated with incrementally higher mortality risk one year after transitioning to dialysis (Pre-ESRD hypoglycemia: Hazard ratios: 1.28 (1.18⁻1.38, p < 0.001), 1.64 (1.49⁻1.81, p < 0.001) for one, two hypoglycemia-related hospitalizations, respectively; post-ESRD hypoglycemia: HRs of 1.56 (1.40⁻1.73, p < 0.001), 1.72 (1.39⁻2.12, p < 0.001) for one, two hypoglycemia-related hospitalizations, respectively (reference group: no hypoglycemia related hospitalization)). CONCLUSIONS: Among advanced DKD patients, we observed a progressive elevated risk of hypoglycemia during the critical dialysis transition period. Increased frequency of severe hypoglycemia-related hospitalizations was associated with higher mortality risk one year after transitioning to dialysis. Further study of glycemic management strategies which prevent hypoglycemia during the critical transition period are warranted.

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.

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.

Effect of celastrol on the progression of polycystic kidney disease in a Pkd1-deficient mouse model.

AIMS: Celastrol, a naturally occurring pentacyclic triterpene, has attracted considerable interest because it exhibits potent anti-inflammatory and anti-tumor properties. However, the effects of celastrol in autosomal dominant polycystic kidney disease (ADPKD) remain uninvestigated. MAIN METHODS: We determined the effects of celastrol on ADPKD progression in a novel Pkd1-hypomorphic mouse model by intraperitoneal injection (postnatal day 35-63). KEY FINDINGS: Pkd1 miRNA transgenic (Pkd1 miR TG) mice treated with 1 mg/kg/day of celastrol exhibited a lower renal cystic index (by 21.5%) than the vehicle-treated controls, but the fractional kidney weights and blood urea nitrogen levels were not significantly affected with celastrol treatment. At a high dose (2 mg/kg/day), celastrol caused marginal weight loss in the treated mice and had no significant effect on renal cystogenesis, thus indicating a potential toxic effect. We further identified that celastrol increased the phosphorylation level of adenosine monophosphate-activated protein kinase (AMPK) in the cystic kidneys. Moreover, celastrol reduced the renal mRNA expression levels of tumor necrosis factor-α, interleukin-1ß, P2RX7, F4/80, CD68, transforming growth factor-ß, collagen-1, and fibronectin, which were high in the Pkd1 miR TG mice. Immunohistological analysis revealed that celastrol suppressed macrophage infiltration in the cystic kidneys; however, the renal fibrosis scores and proliferation indices remained high. SIGNIFICANCE: These results indicate that celastrol could be a potent anti-inflammatory agent and a natural AMPK enhancer. However, celastrol has only modest effects on renal cystogenesis and has a narrow therapeutic window. Further studies are needed to clarify whether celastrol has the potential for the treatment of ADPKD.