METTL3-Mediated N6-methyladenosine mRNA Modification and cGAS-STING Pathway Activity in Kidney Fibrosis.

BACKGROUND: Chemical modifications on RNA profoundly impact RNA function and regulation. m6A, the most abundant RNA modification in eukaryotes, plays a pivotal role in diverse cellular processes and disease mechanisms. However, its importance is understudied in human chronic kidney disease (CKD) samples regarding its influence on pathological mechanisms. METHODS: LC-MS/MS and Methylated RNA Immunoprecipitation (MeRIP) sequencing were utilized to examine alterations in m6A levels and patterns in CKD samples. Overexpression of the m6A writer METTL3 in cultured kidney tubular cells was performed to confirm the impact of m6A in tubular cells and explore the biological functions of m6A modification on target genes. Additionally, tubule-specific deletion of Mettl3 (Ksp-Cre Mettl3f/f) mice and the use of anti-sense oligonucleotides inhibiting Mettl3 expression were utilized to reduce m6A modification in an animal kidney disease model. RESULTS: By examining 127 human CKD samples, we observed a significant increase in m6A modification and METTL3 expression in diseased kidneys. Epitranscriptomic analysis unveiled an enrichment of m6A modifications in transcripts associated with the activation of inflammatory signaling pathways, particularly the cGAS-STING pathway. m6A hypermethylation increased mRNA stability in cGAS and STING1, as well as elevated the expression of key proteins within the cGAS-STING pathway. Both the tubule-specific deletion of Mettl3 and the use of anti-sense oligonucleotides to inhibit Mettl3 expression protected mice from inflammation, reduced cytokine expression, decreased immune cell recruitment, and attenuated kidney fibrosis. CONCLUSIONS: Our research revealed heightened METTL3-mediated m6A modification in fibrotic kidneys, particularly enriching the cGAS-STING pathway. This hypermethylation increased mRNA stability for cGAS and STING1, leading to sterile inflammation and fibrosis.

FHL2 in arterial medial calcification in chronic kidney disease.

BACKGROUND AND HYPOTHESIS: Arterial medial calcification (AMC) is a common complication in individuals with chronic kidney disease (CKD), which can lead to cardiovascular morbidity and mortality. The progression of AMC is controlled by a key transcription factor called runt-related transcription factor 2 (RUNX2), which induces vascular smooth muscle cells (VSMCs) transdifferentiation into a osteogenic phenotype. However, RUNX2 has not been targeted for therapy due to its essential role in bone development. The objective of our study was to discover a RUNX2 coactivator that is highly expressed in arterial VSMCs as a potential therapy for AMC. METHODS: We employed transcriptomic analysis of human data and an animal reporter system to pinpoint FHL2 as a potential target. Subsequently, we investigated the mRNA and protein expression patterns of FHL2 in the aortas of both human and animal subjects with CKD. To examine the role of FHL2 in the RUNX2 transcription machinery, we conducted coimmunoprecipitation (Co-IP) and chromatin immunoprecipitation (ChIP) experiments. Next, we manipulated FHL2 expression in cultured VSMCs to examine its impact on high phosphate-induced transdifferentiation. Finally, we employed FHL2 null mice to confirm the role of FHL2 in the development of AMC in vivo. RESULTS: Among all the potential RUNX2 cofactor, FHL2 displays selective expression within the cardiovascular system. In the context of CKD subjects, FHL2 undergoes upregulation and translocation from the cytosol to the nucleus of arterial VSMCs. Once in the nucleus, FHL2 interacts structurally and functionally with RUNX2, acting as a coactivator of RUNX2. Notably, the inhibition of FHL2 expression averts transdifferentiation of VSMCs into an osteogenic phenotype and mitigates aortic calcification in uremic animals, without causing any detrimental effects on the skeletal system. CONCLUSION: These observations provide evidence that FHL2 is a promising target for treating arterial calcification in patients with CKD.

How renal toxins respond to renal function deterioration and oral toxic adsorbent in pH-controlled releasing capsule.

The number of patients with chronic kidney disease (CKD) is increasing. Oral toxin adsorbents may provide some value. Several uremic toxins, including indoxyl sulfate (IS), p-cresol (PCS), acrolein, per- and poly-fluoroalkyl substances (PFAS), and inflammation markers (interleukin 6 [IL-6] and tumor necrosis factor [TNF]-alpha) have been shown to be related to CKD progression. A total of 81 patients taking oral activated charcoal toxin adsorbents (AC-134), which were embedded in capsules that dissolved in the terminal ileum, three times a day for 1 month, were recruited. The renal function, hemoglobulin (Hb), inflammation markers, three PFAS (PFOA, PFOS, and PFNA), and acrolein were quantified. Compared with the baseline, an improved glomerular filtration rate (GFR) and significantly lower acrolein were noted. Furthermore, the CKD stage 4 and 5 group had significantly higher concentrations of IS, PCS, IL-6, and TNF but lower levels of Hb and PFAS compared with the CKD Stage 3 group at baseline and after the intervention. Hb was increased only in the CKD Stage 3 group after the trial (p = .032). Acrolein did not differ between the different CKD stage groups. Patients with improved GFR (responders) (about 77%) and nonresponders had similar baseline GFR. Responders had higher acrolein and PFOA levels throughout the study and a more significant reduction in acrolein, indicating a better digestion function. Both the higher PFOA and lower acrolein may be related to improved eGFR (and possibly to improvements in proteinuria, which we did not measure. Proteinuria is associated with PFAS loss in the urine), AC-134 showed the potential to improve the GFR and decrease acrolein, which might better indicate renal function change. Future studies are needed with longer follow-ups.

Comparative analysis of hemodialysis and peritoneal dialysis on the risk of new onset diabetes mellitus.

BACKGROUND: Diabetes mellitus is a significant risk factor for cardiovascular events and mortality in dialysis patients. The impact of different dialysis modalities on the risk of new onset diabetes mellitus (NODM) remains a subject of debate. Previous studies did not adequately account for critical confounding factors such as pre-dialysis glycemic status, medication use, and nutritional status, which may influence the association between dialysis modality and NODM risk. METHODS: We conducted a retrospective cohort study of 1426 non-diabetic end-stage renal disease (ESRD) patients who underwent either hemodialysis (HD) or peritoneal dialysis (PD) at a single medical center. We used different statistical methods, adjusting for potential confounding factors, and accounted for competing risk of death. RESULTS: Over 12 years, 331 patients (23 %) developed NODM. After adjusting for potential confounding factors and mortality, PD patients had a significantly higher risk of NODM compared to HD patients (adjusted HR 1.52, p = 0.001). A propensity-matched cohort sensitivity analysis yielded similar results. Among patients with prediabetes, those receiving PD had a 2.93 times higher risk of developing NODM than those receiving HD (p for interaction <0.001), whereas no significant difference was observed among euglycemic patients. NODM was also associated with a 1.78 times increased risk of major cardiovascular events. CONCLUSION: Our study provides evidence that PD treatment may increase the risk of NODM in ESRD patients, particularly among those with preexisting prediabetes. These findings highlight the importance of personalized treatment approaches, and nephrologists should consider prediabetes when choosing the dialysis modality for their patients.

Hybrid Method for Peritoneal Dialysis Catheter Insertion: A New Technique for Improved Outcomes and Reduced Costs.

INTRODUCTION: Peritoneal dialysis (PD) is a well-established treatment choice for end-stage kidney disease (ESKD). While there are several methods for PD catheter insertion, they each have limitations. In this study, we present a new hybrid method for PD catheter insertion and compare it to the conventional laparoscopic method. METHODS: This retrospective study included 171 patients who were undergoing their first PD catheter insertion, and a total of 20% of the enrolled patients had a past medical history of abdominal surgery. Out of these, 101 patients underwent the laparoscopic method and 70 underwent a new invented hybrid method. The study aimed to compare the surgical outcomes, incidence of early and late complications, hospital stay, and medical expenses between the two groups. RESULTS: There were no notable differences in basic demographic features and comorbid conditions between the two groups. The results of our data revealed that the hybrid group had a significantly shorter break-in period and did not require temporary hemodialysis. Additionally, length of hospital stay and medical costs were significantly lower in the hybrid group (all p < 0.05). The incidence of early complications was lower in the hybrid group, while the incidence of late complications was comparable between the two groups. CONCLUSION: Our study demonstrates that the hybrid method of PD catheter insertion provides a safe and efficient alternative to the traditional laparoscopic method, enabling urgent-start PD and reducing hospital stays and medical expenses. Our findings support the use of the hybrid method as a new standard of care for ESKD patients undergoing PD catheter insertion.

Jagged1/Notch2 controls kidney fibrosis via Tfam-mediated metabolic reprogramming.

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.

Dnmt3a and Dnmt3b-Decommissioned Fetal Enhancers are Linked to Kidney Disease.

BACKGROUND: Cytosine methylation is an epigenetic mark that dictates cell fate and response to stimuli. The timing and establishment of methylation logic during kidney development remains unknown. DNA methyltransferase 3a and 3b are the enzymes capable of establishing de novo methylation. METHODS: We generated mice with genetic deletion of Dnmt3a and Dnmt3b in nephron progenitor cells (Six2CreDnmt3a/3b) and kidney tubule cells (KspCreDnmt3a/3b). We characterized KspCreDnmt3a/3b mice at baseline and after injury. Unbiased omics profiling, such as whole genome bisulfite sequencing, reduced representation bisulfite sequencing and RNA sequencing were performed on whole-kidney samples and isolated renal tubule cells. RESULTS: KspCreDnmt3a/3b mice showed no obvious morphologic and functional alterations at baseline. Knockout animals exhibited increased resistance to cisplatin-induced kidney injury, but not to folic acid-induced fibrosis. Whole-genome bisulfite sequencing indicated that Dnmt3a and Dnmt3b play an important role in methylation of gene regulatory regions that act as fetal-specific enhancers in the developing kidney but are decommissioned in the mature kidney. Loss of Dnmt3a and Dnmt3b resulted in failure to silence developmental genes. We also found that fetal-enhancer regions methylated by Dnmt3a and Dnmt3b were enriched for kidney disease genetic risk loci. Methylation patterns of kidneys from patients with CKD showed defects similar to those in mice with Dnmt3a and Dnmt3b deletion. CONCLUSIONS: Our results indicate a potential locus-specific convergence of genetic, epigenetic, and developmental elements in kidney disease development.

The Effect of Far-Infrared Therapy on the Peritoneal Expression of Glucose Degradation Products in Diabetic Patients on Peritoneal Dialysis.

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.

Hereditary bilateral ureteropelvic junction obstruction.

A 42-year-old woman presented with hypertensive crisis and bilateral hydronephrosis. She has a strong family history of ureteropelvic junction obstruction. Ureteropelvic junction obstruction is usually sporadic, unilateral, but inherited UPJO has also been reported.

DNMT1 in Six2 Progenitor Cells Is Essential for Transposable Element Silencing and Kidney Development.

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 (Six2Cre) in mice. RESULTS: Genome-wide methylome analysis indicated dynamic changes on promoters and enhancers during development. Six2CreDnmt3af/f, Six2CreDnmt3bf/f, and Six2CreTet2f/f mice showed no significant structural or functional renal abnormalities. In contrast, Six2CreDnmt1f/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.

PGC-1α Protects from Notch-Induced Kidney Fibrosis Development.

Kidney fibrosis is the histologic manifestation of CKD. Sustained activation of developmental pathways, such as Notch, in tubule epithelial cells has been shown to have a key role in fibrosis development. The molecular mechanism of Notch-induced fibrosis, however, remains poorly understood. Here, we show that, that expression of peroxisomal proliferation g-coactivator (PGC-1α) and fatty acid oxidation-related genes are lower in mice expressing active Notch1 in tubular epithelial cells (Pax8-rtTA/ICN1) compared to littermate controls. Chromatin immunoprecipitation assays revealed that the Notch target gene Hes1 directly binds to the regulatory region of PGC-1α Compared with Pax8-rtTA/ICN1 transgenic animals, Pax8-rtTA/ICN1/Ppargc1a transgenic mice showed improvement of renal structural alterations (on histology) and molecular defect (expression of profibrotic genes). Overexpression of PGC-1α restored mitochondrial content and reversed the fatty acid oxidation defect induced by Notch overexpression in vitro in tubule cells. Furthermore, compared with Pax8-rtTA/ICN1 mice, Pax8-rtTA/ICN1/Ppargc1a mice exhibited improvement in renal fatty acid oxidation gene expression and apoptosis. Our results show that metabolic dysregulation has a key role in kidney fibrosis induced by sustained activation of the Notch developmental pathway and can be ameliorated by PGC-1α.

Risks of Death and Stroke in Patients Undergoing Hemodialysis With New-Onset Atrial Fibrillation: A Competing-Risk Analysis of a Nationwide Cohort.

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 CHA2DS2-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.

Long-Term Outcomes in Critically Ill Septic Patients Who Survived Cardiopulmonary Resuscitation.

OBJECTIVE: To evaluate the long-term survival rate of critically ill sepsis survivors following cardiopulmonary resuscitation on a national scale. DESIGN: Retrospective and observational cohort study. SETTING: Data were extracted from Taiwan's National Health Insurance Research Database. PATIENTS: 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. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: 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. CONCLUSION: 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.

Association between use of oral-antidiabetic drugs and the risk of aortic aneurysm: a nested case-control analysis.

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.

Low air temperature increases the risk of oesophageal variceal bleeding: a population and hospital-based case-crossover study in Taiwan.

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.

Comparative effectiveness of angiotensin-converting-enzyme inhibitors and angiotensin II receptor blockers in patients with type 2 diabetes and retinopathy.

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.

Fixed dose of long-acting erythropoietic stimulating agents at higher frequency improves appetite, reduces inflammation and corrects anaemia in patients on haemodialysis.

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.

Effects on Clinical Outcomes of Adding Dipeptidyl Peptidase-4 Inhibitors Versus Sulfonylureas to Metformin Therapy in Patients With Type 2 Diabetes Mellitus.

BACKGROUND: Recent studies concluded that dipeptidyl peptidase-4 (DPP-4) inhibitors provide glycemic control but also raised concerns about the risk for heart failure in patients with type 2 diabetes mellitus (T2DM). However, large-scale studies of the effects on cardiovascular outcomes of adding DPP-4 inhibitors versus sulfonylureas to metformin therapy remain scarce. OBJECTIVE: To compare clinical outcomes of adding DPP-4 inhibitors versus sulfonylureas to metformin therapy in patients with T2DM. DESIGN: Nationwide study using Taiwan's National Health Insurance Research Database. SETTING: Taiwan. PATIENTS: All patients with T2DM aged 20 years or older between 2009 and 2012. A total of 10,089 propensity score-matched pairs of DPP-4 inhibitor users and sulfonylurea users were examined. MEASUREMENTS: Cox models with exposure to sulfonylureas and DPP-4 inhibitors included as time-varying covariates were used to compare outcomes. The following outcomes were considered: all-cause mortality, major adverse cardiovascular events (MACEs) (including ischemic stroke and myocardial infarction), hospitalization for heart failure, and hypoglycemia. Patients were followed until death or 31 December 2013. RESULTS: DPP-4 inhibitors were associated with lower risks for all-cause death (hazard ratio [HR], 0.63 [95% CI, 0.55 to 0.72]), MACEs (HR, 0.68 [CI, 0.55 to 0.83]), ischemic stroke (HR, 0.64 [CI, 0.51 to 0.81]), and hypoglycemia (HR, 0.43 [CI, 0.33 to 0.56]) compared with sulfonylureas as add-on therapy to metformin but had no effect on risks for myocardial infarction and hospitalization for heart failure. LIMITATION: Observational study design. CONCLUSION: Compared with sulfonylureas, DPP-4 inhibitors were associated with lower risks for all-cause death, MACEs, ischemic stroke, and hypoglycemia when used as add-ons to metformin therapy. PRIMARY FUNDING SOURCE: None.

Four-and-a-Half LIM Domains Protein 2 Is a Coactivator of Wnt Signaling in Diabetic Kidney Disease.

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/ß-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-ß1, activated FHL2 protein and Wnt/ß-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/ß-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 ß-catenin in the podocyte nucleus and that FHL2 protein inhibition can mitigate Wnt/ß-catenin-induced podocytopathy.

Long-term clinical outcome of major adverse cardiac events in survivors of infective endocarditis: a nationwide population-based study.

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.