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Peritoneal dialysis (PD) is a treatment modality for end-stage renal disease (ESRD) patients. Dextrose is a common osmotic agent used in PD solutions and its absorption may exacerbate diabetes mellitus, a common complication of ESRD. PD solutions also contain glucose degradation products (GDPs) that may lead to encapsulating peritoneal sclerosis (EPS), a severe complication of PD. A previous study showed that far-infrared (FIR) therapy improved a patient’s gastrointestinal symptoms due to EPS. Due to limited literature on the matter, this study aims to investigate dialysate GDPs and peritoneal function in diabetic patients on PD. Thirty-one PD patients were enrolled and underwent 40 min of FIR therapy twice daily for six months. We demonstrated the effect of FIR therapy on the following: (1) decrease of methylglyoxal (p = 0.02), furfural (p = 0.005), and 5-hydroxymethylfurfural (p = 0.03), (2) increase of D/D0 glucose ratio (p = 0.03), and (3) decrease of potassium levels (p = 0.008) in both DM and non-DM patients, as well as (4) maintenance and increase of peritoneal Kt/V in DM and non-DM patients, respectively (p = 0.03). FIR therapy is a non-invasive intervention that can decrease dialysate GDPs in PD patients by improving peritoneal transport rate and solute removal clearance, while also maintaining dialysis adequacy.

Background Colistin is widely used in the treatment of nosocomial infections caused by carbapenem-resistant gram-negative bacilli (CR-GNB). Colistin-induced nephrotoxicity is one of the major adverse reactions during colistin treatment. Comparisons of colistin-induced nephrotoxicity between different formulations of colistin are rarely reported. Methods In this retrospective cohort study, we enrolled intensive care unit–admitted patients if they had culture isolates of CR-GNB and underwent intravenous treatment with colistin. The occurrence of acute kidney injury (AKI) during intravenous treatment with colistin was recorded. The occurrence of colistin-induced nephrotoxicity was compared between two formulations of colistin, Locolin®, and Colimycin®. Treatment outcomes associated with the occurrence of colistin-induced nephrotoxicity were also investigated. Results Among 195 patients, 95 who were treated with Locolin® and 100 who were treated with Colimycin® were included for analysis. Patients treated with Locolin® had a higher rate of occurrence of stage 2 (46.3% vs. 32%, p = 0.040) and stage 3 (29.5% vs. 13%, p = 0.005) AKI than did those treated with Colimycin®. In multivariate analysis, the presence of septic shock (adjusted odds ratio [aOR] 2.17, 95% confidence interval [CI] 1.10–4.26) and inappropriate colistin dosage (aOR 2.52, 95% CI 1.00–6.33) were clinical factors associated with colistin-induced nephrotoxicity. Treatment with Colimycin® was an independent factor associated with a lower risk of colistin-induced nephrotoxicity (aOR 0.37, 95% CI 0.18–0.77). The mortality rate was comparable between patients with and without colistin-induced nephrotoxicity. Conclusions The risk of colistin-induced nephrotoxicity significantly varied in different formulations of colistin in critically ill patients. Colistin-induced nephrotoxicity was not associated with increased mortality rate.

Patients with systemic lupus erythematosus (SLE) have a higher risk of vascular complications. This retrospective cohort study aimed to analyze the differences in the risk of arteriovenous fistula or graft (AVF/AVG) dysfunction in hemodialysis patients with and without SLE from Taiwan’s National Health Insurance Database over a 10-year period. AVF/AVG dysfunction is defined as the occurrence of the first episode of intervention after vascular access creation. A total of 1366 HD patients with SLE had higher incidence rates of AVF/AVG dysfunction than 4098 non-SLE HD patients in the following 4 periods: (1) after 1 year (incidence rates = 15.21% and 13.01%, respectively; subdistribution hazard ratio (SHR) = 1.16; P = 0.007), (2) 1st-to-10th-year period (15.36% and 13.25%; SHR = 1.16; P = 0.007), (3) 5th-to-10th-year period (11.91% and 8.1%; SHR = 1.42; P = 0.003), and (4) overall period (23.53% and 21.66%; SHR = 1.09; P = 0.027). In conclusion, there were significantly higher incidence rates of AVF/AVG dysfunction in SLE patients during the long-term follow-up period. Vascular access function should be monitored regularly by clinical examinations, especially after 1 year and during 5 to 10 years, to improve AVF/AVG patency and dialysis adequacy in SLE patients undergoing maintenance hemodialysis.

Background The clinical effect of atrial fibrillation (AF)-related ischemic cardiovascular events in patients undergoing peritoneal dialysis (PD) remains uncertain. This study aimed to investigate the risk of ischemic events in patients undergoing PD with new-onset AF compared with that in patients without AF and ascertain the association between the CHA2DS2-VASc score and risk of ischemic stroke. Methods This nationwide, population-based cohort study used data from Taiwan's National Health Insurance Research Database from 1998 to 2011 for patients receiving PD with or without new-onset AF. The clinical endpoints included ischemic stroke, all-cause death, and in-hospital cardiovascular death. Results Patients undergoing PD with new-onset AF (N = 505) had significantly higher risks of ischemic stroke (adjusted hazard ratio [aHR], 1.98; 95% CI, 1.40-2.80), all-cause death (aHR, 1.61; 95% CI, 1.40-1.85), and in-hospital cardiovascular death (aHR, 1.82; 95% CI, 1.50.2.21) compared with those in patients undergoing PD without AF. After considering in-hospital death as a competing risk, AF remained associated with an increased risk of ischemic stroke (hazard ratio [HR], 1.67; 95% CI, 1.17-2.37). The CHA2DS2-VASc score was associated with the risk of ischemic stroke (HR, 1.28; 95% CI, 1.12-1.46). Conclusion The risks of ischemic stroke, all-cause death, and in-hospital cardiovascular death were significantly higher in patients undergoing PD with AF than those in patients without AF. The CHA2DS2-VASc score remained associated with the risk of ischemic stroke in patients undergoing PD with AF.

Ethnopharmacological relevance Ginkgo biloba extract (GbE) is derived from a medicinal plant and suggested as a treatment for diabetic nephropathy (DN), but the mechanism was not clarified. Aim of study The present study investigated whether GbE prevented DN via activation of heme oxygenase (HO)-1. Materials and methods Streptozotocin-induced diabetic mice were fed a high-fat diet to generate DN. Human and murine podocytes were used for the in vitro study. Results GbE improved renal function via decreasing glomerular hypertrophy, the kidney/body weight ratio, and albuminuria in DN mice. GbE reversed the reduction of synaptopodin and nephrin and enhanced HO-1 expression in the kidneys of DN mice. GbE decreased the enhancement of TNF-α, IL-6, fibronectin, and lipid accumulation in the glomeruli of DN mice. GbE attenuated the uptake of oxidized low-density lipoprotein and reduced the production of ROS in high glucose-stimulated podocytes, and HO-1 inhibitor treatment abrogated the protective effects of GbE. Nuclear factor erythroid 2-related factor 2 (Nrf-2) siRNA significantly abolished the beneficial effects of GbE via decreased HO-1 expression and enhanced TNF-α and IL-6 levels. Conclusions GbE protected podocytes against hyperglycemia and prevented the development of DN via Nrf-2/HO-1 activation. Our findings provide further mechanistic insight into the potential use of GbE in clinical DN.

Myofascial pain syndrome (MPS) is a common disorder characterized by muscle pain if myofascial trigger points (MTrP) are stimulated. This study evaluated the effectiveness of far-infrared ray (FIR) patches in reducing the severity of pain in patients with MPS.A double-blind, randomized controlled study involving 125 patients with MPS and 201 MTrPs located in the trapezius muscle. A FIR patch was applied to 98 MTrPs for 24h in the intervention group (61 patients) and a placebo patch was applied to 91 MTrPs in the control group (57 patients) at the end. Pain intensity was measured using the visual analogue scale (V) while pressure pain threshold (P) and maximal pain tolerance (T) were measured using an algometer before and after treatment.The mean age of the patients was 37.16 years old and 67% were female. There was a positive correlation between P and T (p0.001). Older Age was associated with higher P and T due to poor skin sensitivity (p0.001). V improved significantly in both groups to a similar extent, but only in the intervention group, P and T decreased significantly (which implied better skin sensitivity) (p0.05). P and T decreased the most in the female group aged over 35, probably due to thinner skin in this subgroup.FIR and placebo patches were equally effective at relieving pain (with decreased V), but P and T dropped only in the intervention group with FIR patches. This probably resulted from FIR penetrated only to the skin layer and improved skin sensitivity with more blood circulation, but the muscle remained unaffected. Further studies should investigate the effect of longer exposure or higher energy applications.

Background: The effect of warfarin on the risk of cardiovascular (CV) disease is unknown among chronic hemodialysis patients with atrial fibrillation (HD-AF). Methods: Population-based propensity score and prescription time-distribution matched cohort study including 6719 HD-AF patients with CHA2DS2-VASc score ≥ 2 were divided into warfarin users and nonusers and followed-up for CV events and death. Results: Warfarin treatment in HD-AF patients with AF preceding HD was associated with higher risks of developing congestive heart failure [hazard ratio (HR) = 1.82, 95% confidence interval (CI) = 1.29–2.58, p

Anaemia is an important issue in patients undergoing haemodialysis. We aimed to identify a better dosing schedule of a fixed monthly dose of continuous erythropoietin receptor activator (CERA) in patients with chronic kidney disease (CKD) on haemodialysis. The CERA dosing schedule included 100 μg once monthly for 2 months, 50 μg twice monthly for 2 months and then 100 μg once monthly for two months. The effectiveness was determined by comparing haematocrit, nutritional status (serum protein and albumin) and inflammatory markers (tumour necrosis factor (TNF)-α, interleukin (IL)-1, IL-6 and Hepcidin) at the beginning of the study with those at the end of the study. Forty-seven out of 67 patients completed the trial. At the end, haematocrit was significantly higher (34.51 vs 33.22%, P=.004), levels of inflammatory markers were significantly lower (TNF-α (30.71 vs 35.67 ng/mL, P=.007), IL-6 (5.12 vs 7.95 ng/mL, P=.033), hepcidin (60.39 vs 74.39 ng/mL, P=.002)), blood glucose levels were significantly lower (112.40 vs 139.02 mg/dL, P=.003) and albumin was significantly higher (4.11 vs 3.98, P=.001). Patients with a better than average response had a lower initial number of red blood cells (3.3 vs 3.6 × 10(6) /mm(3) , P=.025) and a lower IL-1 (3.8 vs 12.9 ng/mL, P=.01). They also had significantly lower blood glucose levels at the end. (91.3 vs 124.0 mg/dL, P=.03). We demonstrate that a fixed monthly dose of CERA at a twice monthly dosing schedule improves nutrition, reduces the inflammation and corrects anaemia in patients on haemodialysis. This finding may provide a new strategy for treating CKD-related anaemia.

To evaluate the long-term survival rate of critically ill sepsis survivors following cardiopulmonary resuscitation on a national scale.Retrospective and observational cohort study.Data were extracted from Taiwan's National Health Insurance Research Database.A total of 272,897 ICU patients with sepsis were identified during 2000-2010. Patients who survived to hospital discharge were enrolled. Post-discharge survival outcomes of ICU sepsis survivors who received cardiopulmonary resuscitation were compared with those of patients who did not experience cardiopulmonary arrest using propensity score matching with a 1:1 ratio.None.Only 7% (n = 3,207) of sepsis patients who received cardiopulmonary resuscitation survived to discharge. The overall 1-, 2-, and 5-year postdischarge survival rates following cardiopulmonary resuscitation were 28%, 23%, and 14%, respectively. Compared with sepsis survivors without cardiopulmonary arrest, sepsis survivors who received cardiopulmonary resuscitation had a greater risk of all-cause mortality after discharge (hazard ratio, 1.38; 95% CI, 1.34-1.46). This difference in mortality risk diminished after 2 years (hazard ratio, 1.11; 95% CI, 0.96-1.28). Multivariable analysis showed that independent risk factors for long-term mortality following cardiopulmonary resuscitation were male sex, older age, receipt of care in a nonmedical center, higher Charlson Comorbidity Index score, chronic kidney disease, cancer, respiratory infection, vasoactive agent use, and receipt of renal replacement therapy during ICU stay.The long-term outcome was worse in ICU survivors of sepsis who received in-hospital cardiopulmonary resuscitation than in those who did not, but this increased risk of mortality diminished at 2 years after discharge.

Renin-angiotensin-aldosterone system blockers are the preferred antihypertensive medications in patients with diabetes and prior stroke. This study aimed to compare the effects of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) in terms of major adverse cardiac events (MACEs) in patients with diabetes who survived ischemic stroke.We conducted an observational, nationwide, propensity score-matched cohort study using Taiwan's National Health Insurance Research Database. Patients aged at least 20 years with type 2 diabetes who initiated ACEI (n = 15,959) or ARB (n = 23,929) use within 90 days after discharge for first ischemic stroke between January 2000 and December 2011 were allocated to ACEI and ARB groups, respectively. The primary outcomes were MACEs (myocardial infarction, ischemic stroke, and cardiovascular mortality). The secondary outcomes were hospitalization for acute kidney injury and hyperkalemia. Intention-to-treat and as-treated models were used.Intention-to-treat analysis showed no significant difference between the ACEI and ARB groups in the outcomes of MACEs [hazard ratio (HR), 0.99; 95% confidence interval (CI), 0.95-1.04], including ischemic stroke (HR, 1.01; 95% CI, 0.97-1.06), myocardial infarction (HR, 1.06; 95% CI, 0.95-1.18), and cardiovascular mortality (HR, 0.98; 95% CI, 0.91-1.06). As-treated analysis produced similar results. Additionally, the groups showed no difference in the risk of hospitalization for acute kidney injury or hyperkalemia.Our study supports the hypothesis that the risks of MACEs and two additional secondary outcomes in patients with diabetes who survived ischemic stroke did not differ according to ACEI versus ARB use.

Background— Whether oral anticoagulant use should be considered in patients undergoing hemodialysis with atrial fibrillation (AF) remains controversial because of the uncertainty regarding risk-benefit assessments. The purpose of this study was to investigate the risk of ischemic stroke in patients undergoing hemodialysis with new-onset AF, in comparison with those without arrhythmia. Methods and Results— This nationwide, population-based, propensity score–matched cohort study used data from Taiwan’s National Health Insurance Research Database during 1998 to 2011 for patients on hemodialysis with new-onset nonvalvular AF and matched subjects without arrhythmia. The clinical end points were ischemic stroke (fatal or nonfatal), all-cause death, and other serious adverse cardiovascular events. In comparison with the matched cohort, patients with AF (n=6772) had higher risks of ischemic stroke (adjusted hazard ratio [aHR], 1.27; 95% confidence interval [CI], 1.13–1.43), all-cause death (aHR, 1.59; 95% CI, 1.52–1.67), in-hospital cardiovascular death (aHR, 1.83; 95% CI, 1.71–1.94), myocardial infarction (aHR, 1.33; 95% CI, 1.17–1.51), and hospitalization for heart failure (aHR, 1.90; 95% CI, 1.76–2.05). After considering in-hospital death as a competing risk, AF significantly increased the risk of heart failure (HR, 1.56; 95% CI, 1.45–1.68), but not those of ischemic stroke and myocardial infarction. Additionally, the predictive value of the CHA 2 DS 2 –VASc score for ischemic stroke was diminished in the competing-risk model. Conclusions— The risk of stroke was only modestly higher in patients undergoing hemodialysis with new-onset AF than in those without AF, and it became insignificant when accounting for the competing risk of in-hospital death.

Background The comorbidity profile, especially cancer risk, of narcoleptic patients has seldom been explored. We used a nationwide database to evaluate the risk of cancer among adult narcoleptic patients. Methods We conducted the cohort study using National Health Insurance Research Database from 2000 to 2009. Standardized incidence ratios (SIRs) of cancers were calculated to compare the cancer incidence of the study cohort with that of the general population. Results 2833 narcoleptic patients were identified after excluding patients with antecedent malignancy and age younger than 18 years old. The study cohort was observed for 15,913 person-years during a 10-year period. The median follow-up interval was 5.6 ± 3.0 years. Seventy-four cancers occurred in during the follow-up. The risk of all cancers was found significantly increased in adult narcoleptic patients (SIR 1.32; 95% CI, 1.04–1.66, p = 0.0248). Regarding sex, the overall cancer risk was increased in female patients (SIR 1.52; 95% CI, 1.05–2.13, p = 0.026). Furthermore, females were found to have more head and neck cancers (SIR 6.17; 95% CI, 1.66-15.80, p = 0.009) and gastric cancers (SIR 4.87; 95% CI, 1.31–12.48, p = 0.02). For males, the incidence of overall and specific cancer types was not significantly increased. Conclusions Adult narcoleptic patients had a higher risk for cancer. Further research is warranted to elucidate the mechanism underlying its association.

Diabetic kidney disease (DKD) is a microvascular complication that leads to kidney dysfunction and ESRD, but the underlying mechanisms remain unclear. Podocyte Wnt-pathway activation has been demonstrated to be a trigger mechanism for various proteinuric diseases. Notably, four-and-a-half LIM domains protein 2 (FHL2) is highly expressed in urogenital systems and has been implicated in Wnt/β-catenin signaling. Here, we used in vitro podocyte culture experiments and a streptozotocin-induced DKD model in FHL2 gene-knockout mice to determine the possible role of FHL2 in DKD and to clarify its association with the Wnt pathway. In human and mouse kidney tissues, FHL2 protein was abundantly expressed in podocytes but not in renal tubular cells. Treatment with high glucose or diabetes-related cytokines, including angiotensin II and TGF-β1, activated FHL2 protein and Wnt/β-catenin signaling in cultured podocytes. This activation also upregulated FHL2 expression and promoted FHL2 translocation from cytosol to nucleus. Genetic deletion of the FHL2 gene mitigated the podocyte dedifferentiation caused by activated Wnt/β-catenin signaling under Wnt-On, but not under Wnt-Off, conditions. Diabetic FHL2(+/+) mice developed markedly increased albuminuria and thickening of the glomerular basement membrane compared with nondiabetic FHL2(+/+) mice. However, FHL2 knockout significantly attenuated these DKD-induced changes. Furthermore, kidney samples from patients with diabetes had a higher degree of FHL2 podocyte nuclear translocation, which was positively associated with albuminuria and progressive renal function deterioration. Therefore, we conclude that FHL2 has both structural and functional protein-protein interactions with β-catenin in the podocyte nucleus and that FHL2 protein inhibition can mitigate Wnt/β-catenin-induced podocytopathy.

While Notch signaling has been proposed to play a key role in fibrosis, the direct molecular pathways targeted by Notch signaling and the precise ligand and receptor pair that are responsible for kidney disease remain poorly defined. In this study, we found that JAG1 and NOTCH2 showed the strongest correlation with the degree of interstitial fibrosis in a genome-wide expression analysis of a large cohort of human kidney samples. Transcript analysis of mouse kidney disease models, including folic-acid (FA)–induced nephropathy, unilateral ureteral obstruction (UUO), or apolipoprotein L1 (APOL1)-associated kidney disease, indicated that Jag1 and Notch2 levels were higher in all analyzed kidney fibrosis models. Mice with tubule-specific deletion of Jag1 or Notch2 (Kspcre/Jag1flox/flox and Kspcre/Notch2flox/flox) had no kidney-specific alterations at baseline but showed protection from FA-induced kidney fibrosis. Tubule-specific genetic deletion of Notch1 and global knockout of Notch3 had no effect on fibrosis. In vitro chromatin immunoprecipitation experiments and genome-wide expression studies identified the mitochondrial transcription factor A (Tfam) as a direct Notch target. Re-expression of Tfam in tubule cells prevented Notch-induced metabolic and profibrotic reprogramming. Tubule–specific deletion of Tfam resulted in fibrosis. In summary, Jag1 and Notch2 play a key role in kidney fibrosis development by regulating Tfam expression and metabolic reprogramming., Author summary Chronic kidney disease (CKD) is the ninth leading cause of death in the United States. Kidney fibrosis usually occurs at the final stage of the disease. The Notch signaling pathway is a cell–cell communication pathway, that activated by a ligand (expressed on the signal-sending cell) interacting with and inducing the breakdown of the Notch receptor on the receiving cell. We previously established that Notch signaling in renal tubular epithelial cells (RTECs) plays a key role in kidney fibrosis development. However, the precise ligand and receptor pair that contributes to kidney fibrosis remain unknown. Here, we performed a systematic analysis to define the specific molecular pathways of Notch-induced fibrosis development in RTECs. We found that Jag1 acting together with Notch2 leads to metabolic reprogramming of RTECs via mitochondrial transcription factor A (Tfam), resulting in cell proliferation and dedifferentiation and fibrosis development. Our study suggests that targeting JAG1 or NOTCH2 may have important therapeutic potential for treatment of CKD.

Introduction Proprotein convertase subtilisin/kexin-6 (PCSK6) is a secretory protein that activates corin in the heart. Higher circulating levels of corin are associated with improved cardiovascular outcomes in patients with acute myocardial infarction. This study aimed to determine the role of serum PCSK6 and corin levels in predicting cardiovascular outcomes in patients with suspected coronary artery disease (CAD). Materials and methods In total, 565 patients who had undergone coronary angiography were enrolled. Serum PCSK6 and corin levels were determined before the administration of contrast media. In this study, coronary revascularization, acute myocardial infarction, acute stroke, and death were defined as cardiovascular outcomes. All patients were followed up for at least one year after coronary angiography or until the occurrence of death. Results During a median follow-up of 691 days, 67 patients (15.7%) developed composite cardiovascular outcomes after coronary angiography, including 51 incidents of coronary revascularization, 7 instances of acute myocardial infarction, 2 acute strokes, and 15 deaths. After adjustment for demographic characteristics and all significant variables in the univariate analysis, serum levels of neither PCSK6 nor corin were associated with increased risk for cardiovascular outcomes. This correlation remained insignificant in patients with underlying hypertension, diabetes mellitus, CAD, heart failure, or chronic kidney disease (CKD). However, in patients without CKD, higher serum PCSK6 levels were associated with increased risk for cardiovascular outcomes (hazard ratio 1.380; 95% confidence interval 1.023–1.862). Conclusions We found no association between cardiovascular outcomes and pre-procedural serum levels of PCSK6 or corin in patients undergoing coronary angiography. However, an increased risk was seen in non-CKD patients with higher PCSK6 levels. Further studies are needed to verify these results.

BACKGROUND: Cytosine methylation of regulatory regions, such as promoters and enhancers, plays a key role in regulating gene expression, however, its role in kidney development has not been analyzed. METHODS: To identify functionally important epigenome-modifying enzymes and genome regions where methylation modifications are functionally important for kidney development, we performed genome-wide methylation analysis, expression profiling, and systematic genetic targeting of DNA methyltransferases (Dnmt1, Dnmt3a, and Dnmt3b) and Ten-eleven translocation methylcytosine hydroxylases (Tet2) in nephron progenitor cells (Six2(Cre)) in mice. RESULTS: Genome-wide methylome analysis indicated dynamic changes on promoters and enhancers during development. Six2(Cre)Dnmt3a(f/f), Six2(Cre)Dnmt3b(f/f), and Six2(Cre)Tet2(f/f) mice showed no significant structural or functional renal abnormalities. In contrast, Six2(Cre)Dnmt1(f/f) mice died within 24 hours of birth, from a severe kidney developmental defect. Genome-wide methylation analysis indicated a marked loss of methylation of transposable elements. RNA sequencing detected endogenous retroviral transcripts. Expression of intracellular viral sensing pathways (RIG-I), early embryonic, nonrenal lineage genes and increased cell death contributed to the phenotype development. In podocytes, loss of Dnmt1, Dnmt3a, Dnmt3b, or Tet2 did not lead to functional or structural differences at baseline or after toxic injury. CONCLUSIONS: Genome-wide cytosine methylation and gene expression profiling showed that by silencing embryonic, nonrenal lineage genes and transposable elements, DNMT1-mediated cytosine methylation is essential for kidney development.

Background Higher circulatory corin in patients with cardiac diseases is associated with improved cardiovascular outcomes, and chronic cardiac dysfunction is a well‐known cause of progressive renal dysfunction. This study aimed to determine the role of serum corin in predicting short‐term and long‐term renal outcomes after contrast exposure in patients with suspected coronary artery disease. Methods and Results Four hundred one patients who had received coronary angiography were enrolled. Serum corin levels were determined before administration of contrast media. Contrast‐induced nephropathy was defined as a rise in serum creatinine of 0.5 mg/dL or a 25% increase from baseline within 48 hours after the procedure. Progressive renal dysfunction was defined as >50% decrease in estimated glomerular filtration rate after discharge. All patients were followed up for at least 1 year or until the occurrence of death after coronary angiography. Overall, contrast‐induced nephropathy occurred in 23 (5.7%) patients. During a median follow‐up of 529 days, 44 (11.0%) cases had subsequent decline in renal function. After adjustment for demographic characteristics, kidney function, traditional risk factors, and medications, lower corin level was found to be independently associated with higher risk for progressive renal dysfunction (hazard ratio, 0.23; 95% confidence interval, 0.12–0.44) but not for contrast‐induced nephropathy. This inverse correlation remained evident in patients with underlying chronic kidney disease, coronary artery disease, or heart failure. Conclusions Lower baseline serum corin was associated with higher risk of renal function decline in patients undergoing coronary angiography. Further studies are needed to verify these results.

Perfluorooctanesulfonate (PFOS) and perfluorooctanoic acid (PFOA) are commonly used perfluorinated chemicals (PFCs). PFCs are mainly excreted by urine. Uremic patients tend to accumulate toxins in their body and have poor functional status. We investigated the associations between PFCs and the clinical profile of uremic patients under hemodialysis (HD). Liquid chromatography tandem mass spectrometry coupled with isotope dilution was used to quantify PFOA and PFOS. We enrolled 126 patients under regular HD. Compared with previous research, the concentration of PFOA was lower, but that of PFOS was higher in uremic patients than in the general population. The levels of PFOA and PFOS in uremic patients before dialysis were 0.52 (ng/ml) and 21.84 (ng/ml) respectively. The PFOA level remained unchanged but that of PFOS decreased to1.85 ng/mL after dialysis. PFOS can be removed by HD. Patients using hypertensive medication had a lower PFOS then those who did not. The PFOS level was negatively correlated with the duration of the HD session and patient performance status, but positively correlated with levels of cholesterol, chloride (an indicator of acidemia), ferritin, and total protein. (p

Objectives There is a lack of consensus on the risk factors for hernia formation, and the impact on peritoneal dialysis (PD) survival has seldom been studied. Methods This was a population-based study and all collected data were retrieved from the National Health Insurance Research Database of Taiwan. Patients who commenced PD between January 1998 and December 2006 were screened for inclusion. Multiple logistic regression and Cox proportional hazards models were applied to estimate the predictors for hernia formation and determine the predictors of PD withdrawal. Results A total of 6,928 PD patients were enrolled and followed until December 2009, with 631 hernia events and 391 hernioplasties being registered in 530 patients (7.7%). The incidence rate was 0.04 hernias/patient/year. Longer PD duration (per 1 month increase, hazard ratio (HR) 1.019) and history of mitral valve prolapse (MVP) (HR 1.584) were independent risk factors for hernia formation during PD, and female gender (HR 0.617) was a protective factor. On the other hand, there were 4,468 PD withdrawals, with cumulative incidence rates of 41% at 1 year, 66% at 3 years, and 82% at 5 years. Independent determinants for cumulative PD withdrawal included hernia formation during PD (HR 1.154), age (per 1 year increase, HR 1.014), larger dialysate volume (per 1 liter increase, HR 0.496), female gender (HR 0.763), heart failure (HR 1.092), hypertension (HR 1.207), myocardial infarction (HR 1.292), chronic obstructive pulmonary disease (COPD) (HR 1.227), cerebrovascular accident (CVA) (HR 1.364), and history of MVP (HR 0.712) Conclusions Prolonged PD duration was a risk factor for hernia formation, and female gender was protective. Hernia formation during PD therapy may increase the risk of PD withdrawal.

Objective Acute kidney injury is a common and serious problem after cardiac surgery. Postoperative acute kidney injury is independently associated with in-hospital mortality and long-term morbidity, even after adjustment for comorbid diseases. Chronic kidney disease has been recognized as a strong risk factor of acute kidney injury after cardiac surgery. The association between proteinuria and postcardiotomy acute kidney injury in patients with preserved glomerular filtration rate remains uncertain. Methods Patients with an estimated glomerular filtration rate greater than 60 mL/min/1.73 m 2 who underwent cardiac surgery between January 2003 and December 2007 in a tertiary medical center were retrospectively analyzed. Dipstick urinalysis was performed before surgery. Proteinuria was categorized into negative, trace, 1+, 2+, or 3+. Postoperative acute kidney injury was defined by the Acute Kidney Injury Network criteria. Multinomial logistic regression was used to clarify whether proteinuria is an independent risk factor of postoperative acute kidney injury. Results A total of 1246 patients were included in this study, with a mean estimated glomerular filtration rate of 80 ± 13 mL/min/1.73 m 2 . Proteinuria was present in 290 patients (23.4%). Postoperative acute kidney injury developed in 434 patients (34.8%), and 36 patients (2.9%) required renal replacement therapy. Proteinuria was independently associated with all stages of postcardiotomy acute kidney injury and dialysis-requiring acute kidney injury. The crude risk of acute kidney injury was greater in patients with a higher grade of proteinuria. In subgroup analysis for gender, diabetes, and surgical type, preoperative proteinuria remains a strong risk factor of acute kidney injury after cardiac surgery. Conclusions Urine analysis is usually neglected before cardiac surgery despite the fact that proteinuria is the earliest manifestation of kidney dysfunction. In the current study, we show that urine protein is strongly and independently associated with postoperative acute kidney injury in subjects with preserved estimated glomerular filtration rate. These data suggest that such a relatively simple and clinically easy to use tool as a urinary dipstick may be useful to identify patients at high risk of acute kidney injury before cardiac surgery.

Summary Objective The potential association between healthcare workers (HCWs) and the risk of clinically active tuberculosis (TB) in countries with intermediate TB burdens remains unclear. Methods A nationwide, population-based cohort study was performed by using Taiwan National Health Insurance Database during 2000–2010. We included HCWs and non-HCWs without history of tuberculosis matched at a 1:1 ratio according to age, sex, monthly income, underlying comorbidities, and concomitant medications. All subjects were followed from the date of enrollment until TB occurrence, death, or 31 December 2010. Results The study population comprised 11,811 healthcare workers and 11,811 matched subjects. 62 HCWs and 38 control subjects developed TB during a median follow-up period of 9.4 years. The incidence of TB was higher among HCWs than among matched subjects (61.08 vs . 37.81 per 100,000 person-years). The risk of TB was also greater among HCWs (adjusted hazard ratio [aHR], 1.62; 95% confidence interval [CI], 1.08–2.43), particularly for pulmonary TB in comparison with extrapulmonary TB (aHR, 1.56; 95% CI, 1.02–2.39). Among different job categories of HCWs, we found that only nurses had a significantly increased risk of developing TB (aHR, 2.55; 95% CI, 1.37–4.72) compared to the matched cohort. Conclusions HCWs are associated independently with a higher risk of developing TB in this intermediate-burden country. Therefore, the importance of TB surveillance among HCWs should be emphasized.

Background— Substantial infective endocarditis (IE)–related morbidity and mortality may occur even after successful treatment. However, no previous study has explored long-term hard end points (ie, stroke, myocardial infarction, heart failure, cardiovascular death) in addition to all-cause mortality in IE survivors. Methods and Results— A nationwide population-based cohort study was conducted among IE survivors identified with the use of the Taiwan National Health Insurance Research Database during 2000 to 2009. IE survivors were defined as those who survived after discharge from first hospitalization with a diagnosis of IE. A total of 10 116 IE survivors were identified. IE survivors were matched to control subjects without IE at a 1:1 ratio through the use of propensity scores. The primary outcomes were stroke, myocardial infarction, readmission for heart failure, and sudden cardiac death or ventricular arrhythmia. The secondary outcomes were repeat IE and all-cause mortality. Compared with the matched cohort, IE survivors had higher risks of ischemic stroke (adjusted hazard ratio [aHR], 1.59; 95% confidence interval [CI], 1.40–1.80), hemorrhagic stroke (aHR, 2.37; 95% CI, 1.90–2.96), myocardial infarction (aHR, 1.44; 95% CI, 1.17–1.79), readmission for heart failure (aHR, 2.24; 95% CI, 2.05–2.43), sudden death or ventricular arrhythmia (aHR, 1.69; 95% CI, 1.44–1.98), and all-cause death (aHR, 2.27; 95% CI, 2.14–2.40). Risk factors for repeat IE were older age, male sex, drug abuse, and valvular replacement after an initial episode of IE. Conclusion— Despite treatment, the risk of long-term major adverse cardiac events was substantially increased in IE survivors.

Diabetic nephropathy is characterized by excessive deposition of extracellular matrix protein and disruption of the glomerular filtration barrier. Matrix metalloproteinases (MMPs) affect the breakdown and turnover of extracellular matrix protein, suggesting that altered expression of MMPs may contribute to diabetic nephropathy. Here we used an MMP-9 gene knockout mouse model, with in vitro experiments and clinical samples, to determine the possible role of MMP-9 in diabetic nephropathy. After 6 months of streptozotocin-induced diabetes, mice developed markedly increased albuminuria, glomerular and kidney hypertrophy, and thickening of the glomerular basement membrane. Gelatin zymographic analysis and western blotting showed that there was enhanced MMP-9 protein production and activity in the glomeruli. However, MMP-9 knockout in diabetic mice significantly attenuated these nephropathy changes. In cultured podocytes, various cytokines related to diabetic nephropathy including TGF-β1, TNF-α, and VEGF stimulated MMP-9 secretion. Overexpression of endogenous MMP-9 induced podocyte dedifferentiation. MMP-9 also interrupted podocyte cell integrity, promoted podocyte monolayer permeability to albumin, and extracellular matrix protein synthesis. In diabetic patients, the upregulation of urinary MMP-9 concentrations occurred earlier than the onset of microalbuminuria. Thus, MMP-9 seems to play a role in the development of diabetic nephropathy.Kidney International advance online publication, 26 March 2014; doi:10.1038/ki.2014.67.

Background Headaches resulting from proton pump inhibitor (PPI) use could cause discontinuation of PPI in as many as 40% of patients who experience such headaches. Previous studies focusing on acute headache risk from PPI use are rare and limited to clinical trials of a single PPI. Objectives To investigate the association between PPI use and headache with a nationwide population-based case-crossover study. Methods Records containing the first diagnosis of any headache, including migraine and tension-type headaches, were retrieved from Taiwan National Health Insurance Database (1998–2010). We compared the rates of PPI use for cases and controls during time windows of 7, 14, and 28 days. The adjusted self-matched odds ratios (ORs) and 95% confidence intervals (CIs) from a conditional logistic regression model were used to determine the association between PPI use and headache. Results Overall, 314,210 patients with an initial diagnosis of any headache during the study period were enrolled. The adjusted ORs for headache risk after PPI exposure were calculated for three time periods (within 7 days = 1.41, p = 0.002, 95% CI 1.14–1.74; within 14 days = 1.36, p < 0.001, 95% CI 1.16–1.59; within 28 days = 1.20, p = 0.002, 95% CI 1.07–1.35). Subgroup analyses showed female patients had an increased risk of headache. Among PPIs, lansoprazole and esomeprazole had the highest risks of headache incidence, which were similar to that of nitrates. Conclusion PPI usage is associated with an increased risk for acute headache. Female patients and use of lansoprazole or esomeprazole present the greatest risks of headache.

The association between selective serotonin receptor inhibitors (SSRIs) and risk of upper gastrointestinal bleeding remains controversial. Previous studies have generally evaluated the issue for approximately 3 months, even though the SSRI-mediated inhibition of platelet serotonin concentrations occurs within 7-14 days. The authors explored the risk of upper gastrointestinal bleeding after short-term SSRI exposure by a case-crossover design.The records of psychiatric inpatients with upper gastrointestinal bleeding were retrieved from the Taiwan National Health Insurance Database (1998-2009). Rates of antidepressant use were compared for case and control periods with time windows of 7, 14, and 28 days. The adjusted self-matched odds ratios from a conditional logistic regression model were used to determine the association between SSRI use and upper gastrointestinal bleeding.A total of 5,377 patients with upper gastrointestinal bleeding were enrolled. The adjusted odds ratio for the risk of upper gastrointestinal bleeding after SSRI exposure was 1.67 (95% CI=1.23-2.26) for the 7-day window, 1.84 (95% CI=1.42-2.40) for the 14-day window, and 1.67 (95% CI=1.34-2.08) for the 28-day window. SSRIs with high and intermediate, but not low, affinity for serotonin transporter were associated with upper gastrointestinal bleeding. An elevated risk of upper gastrointestinal bleeding after SSRI exposure was seen in male but not female patients.Short-term SSRI use (7-28 days) is significantly associated with upper gastrointestinal bleeding. Gender differences may exist in the relationship between SSRI use and upper gastrointestinal bleeding. Physicians should carefully monitor signs of upper gastrointestinal bleeding even after short-term exposure to SSRIs, as is done with nonsteroidal anti-inflammatory drugs and aspirin.

High uric acid (UA) can act as a pro-oxidant in normal physiological conditions; however, emerging evidence is still debatable with regard to the association between high UA and poor outcomes among chronic hemodialysis (HD) patients. In the present study, 27,229 stable prevalent HD patients were enrolled and divided into four groups according to the quartiles of baseline UA concentration, and 5737 died during a median follow-up of 38 months. Multivariate Cox regression analysis showed that a UA level of 8.1 mg/dL [HR, 1.20, 95% CI (1.10–1.31)] adjusting for baseline demographic and biochemical parameters. Moreover, a UA level of

Introduction: Perfluoro-octanesulfonate (PFOS) and perfluoro-octanoic acid (PFOA) are two toxic perfluorochemicals (PFCs) commonly used as surfactants. PFCs are difficult to be eliminated from the body. We investigated the influence of different dialysis membranes on the concentrations of PFCs in patients under hemodialysis. Method: We enrolled 98 patients. Of these, 58 patients used hydrophobic polysulfone (PS) dialysis membranes, and the other 40 had hydrophilic membranes made by poly-methyl methacrylate (PMMA) or cellulose triacetate (CTA). Liquid chromatography tandem mass spectrometry coupled was used with isotope dilution to quantify PFOA and PFOS. Results: The predialysis concentrations of PFOA and PFOS in patients with hydrophobic PS dialysis membranes were 0.50 and 15.77 ng/mL, respectively, lower than the concentrations of 0.81 and 22.70 ng/mL, respectively, in those who used hydrophilic membranes (such as CTA or PMMA). Older patients have higher PFOS and poorer body function, with lower Karnofsky Performance Status Scale (KPSS) scores. The demographic data of the two groups were similar. However, patients with hydrophobic PS dialysis membranes had lower predialysis aspartate transaminase (AST) (p = 0.036), lower glucose levels (p = 0.017), and better body function (nonsignificantly higher KPSS scores, p = 0.091) compared with patients who used other membranes. These differences may be associated with the effects of different membranes, because PFOA positively correlated with AST, while PFOS negatively correlated with body function. Conclusions: This is the first study comparing PFC levels in uremic patients with different dialysis membrane. PS membrane may provide better clearance of PFCs and may, therefore, be beneficial for patients.

The objective of this study was to evaluate the risks of acute cholecystitis among end-stage renal disease patients and compare the incidence between two dialysis modality.In this retrospective cohort study, records of fifty thousand end-stage renal disease patients older than 20 years of age from 1998 to 2007 and an age, gender, Charlson's score, diabetes, and dyslipidemia matched control cohort were retrieved from Taiwan National Health Insurance Research Database. Hospitalizations for acute cholecystitis were retrieved using ICD-9-CM diagnosis codes and ICD-9-CM operation codes from in-patient claims.The incidence rates were 5.8 per 1000 patient-years in the end-stage renal disease patients and 0.92 per 1000 patient-years in the control group. End-stage renal disease was an independent risk factor for acute cholecystitis. In the end-stage renal disease patients, independent risk factors were old age, higher Charlson's score, diabetes, severe liver disease, atrial fibrillation, and haemodialysis (all p0.05). However, the peritoneal dialysis patients had a higher mortality rate after developing acute cholecystitis.Acute cholecystitis is not uncommon in end-stage renal disease patients. The independent risk factors were older age, higher Charlson's score, atrial fibrillation, severe liver disease, diabetes, and dialysis modality. Haemodialysis patients had a higher risk of acute cholecystitis than PD patients.

Background There has been no large-scale population-based study on the incidence and clinical manifestations of second primary cancer (SPC) after diagnosis of hepatocellular carcinoma (HCC). Aims This study aimed to evaluate the incidence and the risk factors of SPC following HCC diagnosis. Method This study used data from the National Health Insurance Research Database of Taiwan to identify all HCC patients from 1 January 1997 to 31 December 2006. Cases of SPC were gathered using the ICD9-CM codes of 140–208.91. Standardized incidence ratios (SIRs) were conducted for incidence of SPC in HCC survivors. Competing-risks regression with adjustment of death was used to analyse the risk factors of SPC. Results From 45 976 HCC patients, 749 (1.6%) developed SPC after 90 days of HCC diagnosis. Male HCC patients had higher risks of gastric, biliary, urinary bladder, kidney and haematological cancers compared to the general male population. Female patients had higher incidences of biliary tract, kidney and bone and soft tissue cancers. Older age and chronic kidney disease (CKD) were independent factors predicting SPC. Conclusions SPC in patients with HCC is not rare in Taiwan. Urinary bladder cancer and renal cancer are more specific SPC for HCC patients. Better surveillance strategies for SPC should be established for HCC survivors, especially in the elderly or those with CKD.

Background Patients with end-stage renal disease (ESRD) are at high risk of cardiovascular disease and elevated serum homocysteine levels. Although folic acid supplementation has been documented to reduce serum homocysteine levels in ESRD patients, most trials of folic acid therapy for reducing cardiovascular diseases in ESRD patients have failed, mainly because of limited patient numbers. Methods We used the Taiwan National Health Insurance Research Database (NHIRD) to conduct a matched-pair retrospective cohort study to clarify whether folic acid supplementation benefits ESRD patient survival. Patients were divided into a folic acid supplementation group and a control group. All-cause and cardiovascular-related mortality rates between groups were compared. Results In total, 55,636 stable incident hemodialysis patients were identified from the database. Using a propensity score-matched method and intention-to-treat analysis, the survival rate of 17,000 patients with folic acid supplementation was compared with a 1:1 matched control group. The baseline demographic data and comorbid disease incidence between the 2 groups were comparable. During the study period, the mortality rate in the matched pair cohort was 35.5% (n = 6,030) over a mean follow-up period of 3.0 years, corresponding to a mortality rate of 12.8/100 patient-years. The all-cause mortality rates were 12.3 and 13.4/100 patient-years in the folic acid group and control group, respectively (p = 0.005). Conclusions In adult hemodialysis patients, folic acid supplementation improves cardiovascular and all-cause mortality rates.

Objective To investigate whether cluster headache (CH) was a risk factor for depression in a nationwide population-based follow-up study. Background There are few studies about the relationship between CH and depression, and prior research has been limited by cross-sectional studies or small sample sizes. Methods We identified 673 CH patients from the Taiwan National Health Insurance database between 2005 and 2009. The two comparison cohorts included age-, sex- and Charlson’s score-matched migraine patients ( n = 2692) and controls (patients free from migraine or CH, n = 2692). The cumulative incidence of depression was compared among these three cohorts until the end of 2009. We also calculated predictors of depression in the CH cohort. Results After the median 2.5-year follow-up duration, the CH cohort had a greater risk for developing depression compared to the control cohort (adjusted hazard ratio; aHR = 5.6, 95% CI 3.0–10.6, p Conclusion Our results showed that CH is associated with an increased risk for depression. The strength of this association is similar to that of migraine.

Background Pleiotropic effects on cardiovascular protection have been suggested in several oral antidiabetic drugs (OAD). The impacts of OADs on aortic aneurysm (AA) growth have been found in animal studies, but the evidence of their beneficial effects for AA protection in human are lacking. We investigated the relationship between OAD therapy and the risk of developing AA. Methods We conducted a nested case–control analysis using the database extracted from Taiwan’s National Health Insurance Research Database. The database consists of 1.2 million diabetic patients representing the majority of the type 2 diabetes population in Taiwan from 2000 to 2013. Cases were identified as those with either inpatient or outpatient diagnosis code of AA. One control was selected for each case matching on duration of follow-up, age, sex, urbanization, monthly income, severity of diabetes, and risk factor for AA. We identified variable classes of OADs, including metformin, sulfonylureas, thiazolidinedione (TZD), alpha-glucosidase inhibitors, meglitinide, dipeptidyl peptidase-4 (DPP-4) inhibitors prior to the development of AA. Results A total of 4468 cases diagnosed with AA and 4468 matched controls were identified. Metformin use, sulfonylurea use, and TZD were associated with lower risk of developing AA, odds ratio [OR] 0.72 (95 % confidence interval [CI] 0.64–0.80), 0.82 (95 % CI 0.74–0.92), and 0.82 (95 % CI 0.69–0.98), respectively. The effects of metformin and sulfonylurea on AA were dose responsive. Neither alpha-glucosidase inhibitors (OR 0.95; 95 % CI 0.81–1.11) nor DPP-4 inhibitors (OR 0.85; 95 % CI 0.68–1.07) was significantly associated with AA events. Conclusions Metformin, sulfonylurea, and TZD treated patients were associated with lower risks of AA development, but not DPP-4 inhibitors or alpha-glucosidase inhibitor. The protective effects of hypoglycemic agents are further confirmed by the dose responsive relations in metformin and sulfonylurea groups.

Background: Angiotensin-converting-enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are effective treatments for diabetic retinopathy, but randomized trials and meta-analyses comparing their effects on macrovascular complications have yielded conflicting results. We compared the effectiveness of these drugs in patients with pre-existing diabetic retinopathy in a large population-based cohort. Methods: We conducted a propensity score–matched cohort study using Taiwan’s National Health Insurance Research Database. We included adult patients prescribed an ACE inhibitor or ARB within 90 days after diagnosis of diabetic retinopathy between 2000 and 2010. Primary outcomes were all-cause death and major adverse cardiovascular events (myocardial infarction, ischemic stroke or cardiovascular death). Secondary outcomes were hospital admissions with acute kidney injury or hyperkalemia. Results: We identified 11 246 patients receiving ACE inhibitors and 15 173 receiving ARBs, of whom 9769 patients in each group were matched successfully by propensity scores. In the intention-to-treat analyses, ARBs were similar to ACE inhibitors in risk of all-cause death (hazard ratio [HR] 0.94, 95% confidence interval [CI] 0.87–1.01) and major adverse cardiovascular events (HR 0.95, 95% CI 0.87–1.04), including myocardial infarction (HR 1.03, 95% CI 0.88–1.20), ischemic stroke (HR 0.94, 95% CI 0.85–1.04) and cardiovascular death (HR 1.01, 95% CI 0.88–1.16). They also did not differ from ACE inhibitors in risk of hospital admission with acute kidney injury (HR 1.01, 95% CI 0.91–1.13) and hospital admission with hyperkalemia (HR 1.01, 95% CI 0.86–1.18). Results were similar in as-treated analyses. Interpretation: Our study showed that ACE inhibitors were similar to ARBs in risk of all-cause death, major adverse cardiovascular events and adverse effects among patients with pre-existing diabetic retinopathy.

Acute appendicitis in patients with end-stage renal disease (ESRD) poses a diagnostic challenge. Delayed surgery can contribute to higher morbidity and mortality rates. However, few studies have evaluated this disease among ESRD patients. Our study focused on the lack of data on the incidence and risk factors of acute appendicitis among ESRD patients and compared the outcomes in patients who underwent different dialysis modalities. This national survey was conducted between 1997 and 2005 and included ESRD patients identified from the Taiwan National Health Insurance database. The incidence rate of acute appendicitis in ESRD patients was compared with that in randomly selected age-, sex-, and Charlson comorbidity score-matched non-dialysis controls. A Cox regression hazard model was used to identify risk factors. Among 59,781 incident ESRD patients, matched one-to-one with controls, there were 328 events of acute appendicitis. The incidence rate of 16.9 per 10,000 person-years in the ESRD cohort was higher than that in the control cohort (p = 0.003). The independent risk factors were atrial fibrillation (hazard ratio [HR], 2.08), severe liver disease (HR, 1.74), diabetes mellitus (HR, 1.58), and hemodialysis (HR, 1.74). Compared with the control cohort, subsequent perforation and mortality rates of acute appendicitis were also higher in the ESRD cohorts. There was no effect of dialysis modality on the patient outcomes. ESRD patients had a higher risk for acute appendicitis and poorer outcomes than non-dialysis populations. A careful examination of ESRD patients presenting with atypical abdominal pain to avoid misdiagnosis is extremely important to prevent delayed surgery.

Objective The response of erythropoietic stimulating agents (ESA) in uremic patients may be associated with the changes of biochemical parameters, metal elements and inflammation status during the shift from one ESA to another. Method We compared changes in above mentioned factors after switching from darbepoetin-α (DPO) 20 μg weekly for 10 weeks to continuous erythropoietin receptor activator (CERA) 100 μg monthly for 10 weeks in uremic patients on hemodialysis. The haematocrit (Hct), metal elements and inflammation status are the primary outcome. Subjects included 54 patients without transfusion or bleeding or additional ESAs. Responders (IR, n = 36) were defined as patients with an increase in Hct after the swtich. Result Although there was no significant difference in overall mean Hct after the switch (p = 0.135), there are significantly greater mean number of red blood cells (RBC) (p = 0.006), higher platelet numbers (p = 0.001), larger RBCs (p = 0.017) and higher creatinine (p = 0.04) and total cholesterol (T-CHOL) (p = 0.003) levels. Mean overall aluminium (Al) level decreased significantly (p = 0.001). C-reactive protein (CRP) also decreased (p = 0.016). The overall LDH increased (p = 0.049) and potassium decreased significantly (p = 0.036), which indicating active erythropoiesis. The calcium (Ca) level was significantly higher (p = 0.034) and phosphate was significantly lower (p = 0.028) after the shift. Although there was no significant increase in overall levels of parathyroid hormone (PTH) after the shift (p = 0.061), but the pre-shift and post-shift PTH level was significantly higher in IRs than in non-IRs (p = 0.003 and p = 0.027, respectively). IRs had a significantly lower initial T-CHOL (p = 0.03) and initial CRP (p = 0.012) than non-responders, which may be related to lower inflammation. Conclusion We found the shift from DPO to CERA results in lower Al levels, a reduced inflammatory response, and an increase in RBC number and PTH level in uremic patients on hemodialysis.

Catheter-related blood stream infection (CRBSI) is a major complication in hemodialysis patients. We assessed the efficacy of systemic daptomycin (DPT) plus DPT antibiotic lock therapy (DPT-ALT) for catheter salvage in patients with Gram-positive CRBSIs. This is a retrospective study of hemodialysis patients with tunneled and cuffed hemodialysis catheters. All patients were from a single institution in Taipei and received systemic DPT plus DPT-ALT for the treatment of Gram-positive CRBSI. Successful resolution of CRBSI was implemented. Resolution of fever within 48 hours, negative result of repeated blood cultures after resolution of fever, no clinical evidence of CRBSI relapse and no need for catheter removal were measured. Fifteen hemodialysis patients received DPT-ALT for CRBSI, nine with coagulase-negative Staphylococcus (CONS), two with methicillin-resistant Staphylococcus aureus (MRSA), three with methicillin-sensitive Staphylococcus aureus (MSSA) and one with polymicrobial infections. Systemic DPT plus DPT-ALT cured 11 patients (73.3%). Treatment failed in all three MRSA cases (two with MRSA and one with MRSA + Enterococcus faecalis). Retrospective design and small sample size were the limitations of this study. Systemic DPT plus DPT-ALT appears to be a promising treatment for CRBSI from CONS and MSSA, but not for MRSA CRBSI. Systemic DPT plus DPT-ALT should be considered for patients with CRBSIs caused by certain species.

Although the association of hyperuricemia and cardiovascular diseases is well established by previous research studies, the relationship between gout and deep vein thrombosis (DVT) remains unclear. We conducted a nationwide longitudinal cohort study to investigate the relationship between gout and DVT. We used the Taiwan National Health Insurance Research Database to identify patients with gout diagnosed in Taiwan during 2000–2011, and we followed up these patients to determine the incidence of DVT among them. The association between gout and DVT was analyzed by cox proportional hazard model. The study cohort included 35,959 patients with history of gout attack and 35,959 matched controls without gout attack. During the median follow-up of 7.5 ± 3.6 years, the incidence rate of DVT was significantly higher in patients with gout than that in control group (13.48 versus 9.77 per 104 person-years, p

Background: Compared to the general population, patients with end-stage renal disease (ESRD) have increased peptic ulcer and upper GI bleeding complication rates. However, the risk factors for peptic ulcer among ESRD patients are unknown. Methods: In this retrospective study, we enrolled 827 incident dialysis patients and diagnosed peptic ulcer on the basis of endoscopic findings; information on the morbidities and medical prescription were obtained directly from medical records. A Cox regression hazard model was used to identify risk factors for peptic ulcer. Results: During the 10-year study period, 481 patients underwent an endoscopic exam. Peptic ulcers were detected in 153 patients. Age (p = 0.025), peritoneal dialysis (p = 0.022), diabetes mellitus (p = 0.020), congestive heart failure (p = 0.015), low serum albumin (p = 0.008) and high gamma-glutamyl transpeptidase (γ-GT) levels (p = 0.002) are risk factors for peptic ulcers among ESRD patients. Ulcer severity (p = 0.004) and aspirin prescription (p = 0.043), but not Helicobacter pylori infection, influenced the ulcer recurrence rate. Conclusion: The risk factors for peptic ulcer have some differences between ESRD patients and general population. In patients with high risk of upper GI bleeding, peritoneal dialysis and aspirin should be prescribed with caution.

A 23-year-old Asian man presented to our clinic with pitting edema of the lower limbs for 3 days and a small ulcer on his glans penis. He previously had unprotected sexual intercourse with different male partners and had previously used ketamine and ecstasy (3,4-methylenedioxy-N-methamphetamine). The patient had noticed a diffuse skin rash on his trunk, limbs, palms, and soles since several months ago, and secondary syphilis (RPR: >144 RU, TPHA: 2310 TU) was diagnosed 2 weeks prior to admission. A dose of benzathine penicillin was given upon admission, and fever developed the same evening. One week later, human immunodeficiency virus (HIV) infection was confirmed with western Blot analysis (his CD4-positive lymphocyte count was 500/cumm, viral load was 1230 copies/ml). A urinalysis result was positive for protein (3+) by dipstick. Biochemical examinations revealed hypoalbuminemia and massive proteinuria (blood urea nitrogen level, 15 mg/dl; creatinine level, 0.81 mg/dl; albumin level, 1.2 g/dl; urine protein-to-creatinine ratio, 13.8 g/g; and HbA1c level, 5.8%). Laboratory tests were negative for anti-nuclear antibodies, hepatitis B surface antigen, and anti-hepatitis C virus. Both kidneys were found to be enlarged on sonography. The renal biopsy findings are depicted in Figure 1.

Thiazide diuretics are associated with an increased risk of hyponatremia. The aim of this study was to investigate possible predictors of thiazide-induced hyponatremia. A total of 48 patients admitted to the ward or to the emergency department due to severe thiazide-induced hyponatremia (Na

Although oral antidiabetic drugs (OADs) have been associated with immunomodulation in preclinical studies, little is still known about the association between the use of OADs and the risk of sepsis. Using a cohort of patients, extracted from Taiwan’s National Health Insurance Research Database, with type 2 diabetes who were newly diagnosed between 2010 and 2012 and treated with OADs, we conducted a nested case-control study involving 43,015 cases (patients who were first hospitalized for sepsis) and 43,015 matched controls. Compared with non-use, metformin use was associated with a decreased risk of developing sepsis (adjusted odds ratio [OR] 0.80, 95% confidence interval [CI] 0.77–0.83, P P

Background The spot urine protein/creatinine ratio (UPCR) is proposed to be a substitute for 24-hour urinary protein (24 h-UP). This study is aimed to determine whether the predictive accuracy of 24 h-UP using UPCR can be improved by simply multiplying estimated daily urine creatinine excretion (eUCr) and UPCR together. Methods This study enrolled 120 participants to investigate the correlation between spot UPCR and 24 h-UP. Three sets of spot urine samples were randomly collected throughout the day and night, along with the first morning void. UPCR was weighted by eUCr to investigate the improvement of accuracy in using spot urine samples to predict 24 h-UP. Results There were strong correlation and concordance between UPCR and 24 h-UP irrespective of the time of spot urine sampling, and the correlation, concordance and agreement were improved after multiplying the UPCR value by the eUCr. Greater improvement was found in the subgroups with measured daily urine creatinine excretion ≤ 0.8 g/d and ≥ 1.2 g/d. Conclusions This investigation demonstrated that multiplying UPCR by eUCr can improve the accuracy of only using UPCR to predict 24 h-UP.

Background & Aims Studies concerning seasonal variations and the impact of air temperature on oesophageal variceal bleeding have yielded conflicting results. We aimed to explore the impact of air temperature on the occurrence of variceal bleeding. Methods A case-crossover study design was employed, and two cohorts were used, including the NHI-EVB cohort from the National Health Insurance Research Database of Taiwan from 1 January 1999 to 31 December 2010, and the VGH-EVB cohort from the Taipei Veterans General Hospital, from 4 May 2002 to 31 December 2010. A conditional logistic regression model was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Results In total, 2542 cases from the NHI-EVB cohort and 220 cases from the VGH-EVB cohort were analysed. Our analysis showed that low air temperature (LAT) increased the risk of variceal bleeding regardless of age, sex, decompensated cirrhosis, Child-Pugh classification, aetiology of liver disease and concomitant hepatocellular carcinoma; the lag effect was also observed. The ORs per 5°C decrease in daily mean air temperature were 1.144 (95% CI, 1.060–1.235) for the NHI-EVB cohort and 1.307 (95% CI: 1.031–1.658) for the VGH-EVB cohort. Oesophageal variceal bleeding in patients with small varices, end-stage liver disease score ≧15 or those using non-selective beta blockers was not influenced by air temperature. Conclusions Patients have higher risk of oesophageal variceal bleeding at low air temperature regardless of age, sex, aetiology of cirrhosis, Child-Pugh classification, decompensated cirrhosis and concomitant hepatocellular carcinoma and can be protected by use non-selective beta blockers.

Background The relationship between congenital heart disease (CHD) and malignancies has not been determined. This study aimed to explore the association of CHD with malignancies and examine the risk factors for the development of cancer after a diagnosis of CHD. Patients and methods This nationwide, population-based cohort study on cancer risk evaluated 31,961 patients with newly diagnosed CHD using the Taiwan National Health Insurance Research Database (NHIRD) between 1998 and 2006. The standardized incidence ratios (SIRs) for all and specific cancer types were analyzed, while the Cox proportional hazard model was used to evaluate risk factors of cancer occurrence. Results Among patients with newly diagnosed CHD regardless of ages, 187 (0.6%) subsequently developed cancers after a diagnosis of CHD. Patients with CHD had increased risk of cancer (SIR, 1.45; 95% CI, 1.25-1.67), as well as significantly elevated risks of hematologic (SIR, 4.04; 95% CI, 2.76-5.70), central nervous system (CNS) (SIR, 3.51; 95% CI, 1.92-5.89), and head and neck (SIR, 1.81; 95% CI, 1.03-2.94) malignancies. Age (HR, 1.06; 95% CI, 1.05-1.06) and co-morbid chronic liver disease (HR, 1.91; 95% CI, 1.27-2.87) were independent risk factors for cancer occurrence among CHD patients. Conclusion Patients with CHD have significantly increased cancer risk, particularly hematologic, CNS, and head and neck malignancies. Physicians who care for patients with CHD should be aware of their predisposition to malignancy after the diagnosis of CHD. Further studies are warranted to clarify the association between CHD and malignancies.

Objective Patients with late-onset depression (LOD) have been reported to run a higher risk of subsequent dementia. The present study was conducted to assess whether statins can reduce the risk of dementia in these patients. Methods We used the data from National Health Insurance of Taiwan during 1996–2009. Standardized Incidence Ratios (SIRs) were calculated for LOD and subsequent dementia. The criteria for LOD diagnoses included age ≥65 years, diagnosis of depression after 65 years of age, at least three service claims, and treatment with antidepressants. The time-dependent Cox proportional hazards model was applied for multivariate analyses. Propensity scores with the one-to-one nearest-neighbor matching model were used to select matching patients for validation studies. Kaplan-Meier curve estimate was used to measure the group of patients with dementia living after diagnosis of LOD. Results Totally 45,973 patients aged ≥65 years were enrolled. The prevalence of LOD was 12.9% (5,952/45,973). Patients with LOD showed to have a higher incidence of subsequent dementia compared with those without LOD (Odds Ratio: 2.785; 95% CI 2.619–2.958). Among patients with LOD, lipid lowering agent (LLA) users (for at least 3 months) had lower incidence of subsequent dementia than non-users (Hazard Ratio = 0.781, 95% CI 0.685–0.891). Nevertheless, only statins users showed to have reduced risk of dementia (Hazard Ratio = 0.674, 95% CI 0.547–0.832) while other LLAs did not, which was further validated by Kaplan-Meier estimates after we used the propensity scores with the one-to-one nearest-neighbor matching model to control the confounding factors. Conclusions Statins may reduce the risk of subsequent dementia in patients with LOD.

Background The major gene mutated in autosomal dominant polycystic kidney disease was first identified over 20 years ago, yet its function remains poorly understood. We have used a systems-based approach to examine the effects of acquired loss of Pkd1 in adult mouse kidney as it transitions from normal to cystic state. Methods We performed transcriptional profiling of a large set of male and female kidneys, along with metabolomics and lipidomics analyses of a subset of male kidneys. We also assessed the effects of a modest diet change on cyst progression in young cystic mice. Fatty acid oxidation and glycolytic rates were measured in five control and mutant pairs of epithelial cells. Results We find that females have a significantly less severe kidney phenotype and correlate this protection with differences in lipid metabolism. We show that sex is a major determinant of the transcriptional profile of mouse kidneys and that some of this difference is due to genes involved in lipid metabolism. Pkd1 mutant mice have transcriptional profiles consistent with changes in lipid metabolism and distinct metabolite and complex lipid profiles in kidneys. We also show that cells lacking Pkd1 have an intrinsic fatty acid oxidation defect and that manipulation of lipid content of mouse chow modifies cystic disease. Interpretation Our results suggest PKD could be a disease of altered cellular metabolism., Highlights • Adult female mice have slower kidney disease progression than males in an orthologous Pkd1 model of ADPKD. • Omics and in vitro studies suggest Pkd1 deletion causes cell autonomous metabolic changes and fatty acid oxidation impairment. • Transcriptional sexual dimorphism in mouse kidneys is consistent with lipid metabolism modifying PKD progression in females. • Lower lipid content in diet correlates with slower PKD progression. Autosomal Dominant Polycystic Kidney Disease (ADPKD) is caused by mutations in PKD1 or PKD2 and characterized by the replacement of kidney parenchyma by cysts. Recent studies have identified metabolic differences and increased glycolysis in ADPKD. We now examine the effects of acquired loss of Pkd1 in adult mouse kidney as it transitions from normal to cystic state. We report females have less severe kidney disease and suggest metabolic differences could underlie this protection. Notably, we did not find altered glycolysis, but rather that Pkd1- cells have impaired fatty acid oxidation. We also showed that reducing the fat content in mouse diet correlated with less severe cystic kidney disease. Our results thus support the notion that abnormalities in lipid metabolism are an intrinsic component of ADPKD.

Intensive care unit (ICU)-acquired weakness is a common issue for sepsis survivors that is characterized by impaired muscle strength and causes functional disability. Although inpatient rehabilitation has not been found to reduce in-hospital mortality, the impact of postdischarge rehabilitation on sepsis survivors is uncertain.To investigate the benefit of postdischarge rehabilitation to long-term mortality in sepsis survivors.We conducted a nationwide, population-based, high-dimensional propensity score-matched cohort study using Taiwan's National Health Insurance Research Database. The rehabilitation cohort comprised 15,535 ICU patients who survived sepsis and received rehabilitation within 3 months after discharge between 2000 and 2010. The control cohort consisted of 15,535 high-dimensional propensity score-matched subjects who did not receive rehabilitation within 3 months after discharge. The endpoint was mortality during the 10-year follow-up period.Compared with the control cohort, the rehabilitation cohort had a significantly lower risk of 10-year mortality (adjusted hazard ratio, 0.94; 95% confidence interval, 0.92-0.97; P0.001), with an absolute risk reduction of 1.4 per 100 person-years. The frequency of rehabilitation was inversely associated with 10-year mortality (≥3 vs. 1 course: adjusted hazard ratio, 0.82; P0.001). Compared with the control cohort, improved survival was observed in the rehabilitation cohort among ill patients who had more comorbidities, required more prolonged mechanical ventilation, and had longer ICU or hospital stays, but not among those with the opposite conditions (i.e., less ill patients).Postdischarge rehabilitation may be associated with a reduced risk of 10-year mortality in the subset of patients with particularly long ICU courses.

Background There is substantial debate regarding the development of acute coronary syndrome in patients using proton pump inhibitors (PPIs) combined with clopidogrel. However, data remain limited to address the effect of PPIs alone on the subsequent risk of myocardial infarction (MI). We aimed to explore the subsequent risk of MI in PPI users who had no previous history of MI. Methods The records of inpatients and outpatients with PPI prescriptions were retrieved from the Taiwan National Health Insurance Research Database between 2000 and 2009. We conducted two different study designs, the first using propensity score (PS)-matching analyses and the second using case-crossover analyses. The risk of developing MI for PPI users was analyzed in the PS-matched study. The association between risk of MI and prior PPI exposure was further validated in the case-crossover study. Results In the PS-matched study, we included 126,367 PPI users and 126,367 PS-matched PPI non-users. After 120days of follow-up, PPI use was associated with a 1.58-fold greater risk of MI (adjusted hazard ratio [HR]=1.58, 95% confidence interval [CI]=1.11 to 2.25). In the case-crossover study, adjusted odds ratios of PPI for MI risk were 4.61 (95% CI=1.76 to 12.07) for the 7-day window and 3.47 (95% CI=1.76 to 6.83) for the 14-day window. Conclusions Use of PPIs may be independently associated with an increased risk of MI. However, the benefits of PPIs may greatly outweigh the risks of adverse cardiovascular effects, with number needed to harm of 4357.

End-stage renal disease (ESRD) patients are more prone to infectious disease because of their immunocompromised status. However, the association between pyogenic liver abscess (PLA) and ESRD remains not clear. The aim of our study is to evaluate the incidence, risk factors, and outcomes of PLA in ESRD patients. We recruited all incident ESRD patients from the Taiwan National Health Insurance database from 1998 to 2006. The incidence rate of PLA in ESRD patients was compared with that of a randomly selected non-ESRD control group matched for age, sex gender, Charlson comorbidity score, diabetes mellitus, and cirrhosis. Among the 57,761 incident dialysis patients, there were 538 cases of PLA. The incidence rate of PLA was 18.20 per 10,000 person-years in the ESRD cohort and 6.34 per 10,000 person-years in matched control cohort. The rate of PLA was significantly higher in the ESRD cohort (hazard ratio 3.63, 95% confidence interval 2.83-4.65, P 0.001). The mortality rates of PLA were higher in the ESRD cohort than those in matched control cohort. Diabetes mellitus was an independent risk factor for mortality of PLA. Compared with non-ESRD patients, ESRD patients have a higher risk of PLA and poorer outcomes.

Although statins have been shown to have cholesterol-lowering effects, their pleiotropic benefits on sepsis remain a matter of debate. In addition, the influence of statin potency on sepsis-related mortality has never been explored. The aim of our study was to determine the sepsis outcomes of low- and high-potency statin users and non-users.This nationwide, population-based, propensity score-matched analysis used data from the linked administrative databases of Taiwan's National Health Insurance program. Patients were hospitalized for sepsis between 2000 and 2010. All-cause mortality and major adverse consequences of sepsis, such as in-hospital death, intensive care unit admission, shock events, and the use of mechanical ventilation, were assessed. Patients were divided into high-potency statin users (at least 10 mg rosuvastatin, at least 20 mg atorvastatin, or at least 40 mg simvastatin), low-potency statin users (all other statin treatments), and non-users.A propensity score-matched cohort of 27,792 statin users and 27,792 non-users was included. Of 27,792 statin users, 9,785 (35.2 %) were treated with high-potency statins and 18,007 (64.8 %) were treated with low-potency statins. The 1-year mortality risk was significantly lower among both low-potency [adjusted hazard ratio (aHR) 0.89, 95 % confidence interval (CI) 0.85-0.93] and high-potency (aHR 0.80, 95 % CI 0.75-0.86) statin users compared with non-users. The risks of mortality and adverse consequences of sepsis were lower among high-potency than among low-potency statin users.High-potency statin use is associated with a lower risk of sepsis-related mortality compared with low-potency statin use.