The risk factors and clinical outcomes in hepatitis B seropositive and seronegative renal transplant patients.

INTRODUCTION: Hepatitis B virus (HBV) infection is prevalent in Asia including Taiwan. We retrospectively evaluated the risk of HBV reactivation and clinical outcomes in HBV+ and HBV- kidney transplant recipients. METHODS: Patients who underwent kidney transplantation between January 2004 and December 2021 were reviewed. The outcomes of interest included risks of HBV reactivation and patient/graft survival. RESULTS: We identified 337 patients (47.5 ± 12 years) were enrolled in our final cohort. Fifty-two (15.4%) had HBsAg positive at the time of transplantation. Seventeen developed viral reactivations, with 41.2% of them accompanied by active hepatitis. The graft survival, acute rejection rate, and cancer development after kidney transplantation did not differ in terms of HBsAg status. The Cox multivariate analysis indicated the HBV reactivation risk was increased by a lack of pre-transplant anti-HBV medication [hazard ratio (HR), 5.95; 95% confidence interval (CI), 1.31-27.02; P = 0.021 or an absence of lifelong antiviral therapy [HR, 3.14; 95% CI, 1.01-9.74; P = 0.047] Conclusion: Individuals, independent of HBsAg status, had similar prognosis in terms of patient and graft survival, acute rejection rate, and cancer development. The absence of either pre-transplant anti-HBV medication or lifelong antiviral therapy was significantly associated with an increased risk of HBV reactivation.

Circulating Osteocalcin Fractions are Associated with Vascular Calcification and Mortality in Chronic Hemodialysis Patients.

BACKGROUND: Vascular calcification, a component of chronic kidney disease-mineral and bone disorder (CKD-MBD), is prevalent in patients with end-stage kidney disease (ESKD) and contributes to high mortality. However, the association between the blood level of total osteocalcin (OC) and vascular calcification and mortality remains inconclusive. We, therefore, investigated whether different OC fractions can serve as biomarkers of vascular calcification and mortality in the ESKD population. METHODS: This observational cohort study enrolled patients on maintenance hemodialysis. Plasma carboxylated OC (cOC), uncarboxylated OC (ucOC), and intact parathyroid hormone (PTH) were measured. The percentage of carboxylated OC (%cOC) was calculated as dividing cOC by total OC. The vascular calcification severity was defined by an aortic calcification grade. The patients were followed for three years and one month. RESULTS: A total of 184 patients were enrolled. In the multivariable logistic regression, plasma %cOC, but not cOC or ucOC, was independently associated with the severity of vascular calcification (OR 1.019, p = 0.036). A significant U-shaped correlation was found between plasma %cOC and PTH (p = 0.002). In the multivariable Cox regression, patients with higher plasma %cOC had a higher risk of mortality (quartiles Q4 versus Q1-Q3, HR 1.991 [95% CI: 1.036-3.824], p = 0.039). CONCLUSIONS: In patients undergoing chronic hemodialysis, plasma %cOC positively correlated with vascular calcification and exhibited a U-shaped correlation with PTH. Furthermore, a higher plasma %cOC was associated with increased mortality. These findings suggest that plasma %cOC may serve as a biomarker for CKD-MBD and a predictor of clinical outcomes in chronic hemodialysis patients.

Effect of Renin-Angiotensin-Aldosterone System Blockade on Long-Term Outcomes in Postacute Kidney Injury Patients With Hypertension.

OBJECTIVES: Renal replacement therapy-requiring acute kidney injury frequently occurs in ICUs, which require evidence-based medical attention. However, in the postacute kidney injury patient population, the evidence regarding effective therapies to improve patient outcomes is lacking. Therefore, we aimed to examine whether the renin-angiotensin-aldosterone system blockade is effective in improving renal outcomes in postacute kidney injury patients who experienced temporary renal replacement therapy and have hypertension. DESIGN: A retrospective cohort study. SETTING: A nationwide database in Taiwan. PATIENTS: From January 1, 2000, to December 31, 2013, we identified 8,558 acute kidney injury patients with hypertension in the national registry database. All these patients experienced an acute kidney injury episode, which required temporary renal replacement therapy for at least once. INTERVENTIONS: Users (n = 3,885) and nonusers (n = 4,673) of angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers. MEASUREMENTS AND MAIN RESULTS: We used Cox proportional hazards regression models to analyze hazard ratios for the commencement of end-stage renal disease and all-cause mortality for angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker users (n = 3,885) and nonusers (n = 4,673).In a median follow-up of 4.3 years, 5,880 patients (68.7%) required long-term dialysis, and 4,841 patients (56.6%) died. Compared with postacute kidney injury patients who did not use angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker, angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker users are marginally less likely to progress to end-stage renal disease (adjusted hazard ratio 0.95; 95% CI 0.90-1.01; p = 0.06) and significantly less likely to suffer from all-cause mortality (adjusted hazard ratio 0.93; 95% CI 0.87-0.98; p = 0.011). CONCLUSIONS: In patients who experienced renal replacement therapy-requiring acute kidney injury and have hypertension, angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker use is associated with better survival outcomes compared with nonuser.

Erythropoiesis-stimulating agents in chronic kidney disease: what have we learned in 25 years?

Since the pioneering studies by Eschbach et al in 1987, erythropoiesis-stimulating agents (ESAs) have become the mainstay of anemia therapy in chronic kidney disease (CKD) patients. The introduction of ESAs 25 years ago markedly improved the lives of many patients with CKD, who until then had severe, often transfusion-dependent anemia. However, randomized controlled trials demonstrate an increased risk for cardiovascular events such as stroke, thrombosis, and death at nearly normal hemoglobin concentrations and higher ESA doses in CKD. By contrast, kidney transplant recipients may represent a unique population of CKD patients who may benefit from ESA therapy. This review discusses potential mechanisms involving the erythropoietic and nonerythropoietic effects of ESA treatment and ESA resistance. Further research aimed at elucidating the causal pathways is strongly recommended. Given current knowledge, however, clinical practice should avoid disproportionately high dosages of ESAs to achieve recommended hemoglobin targets, particularly in those with significant cardiovascular morbidity or ESA resistance. The key to CKD anemia management will be individualization of the potential benefits of reducing blood transfusions and anemia-related symptoms against the risks of harm.

Plasma SCUBE2 as a novel biomarker associates with survival outcomes in patients with sepsis-associated acute kidney injury.

BACKGROUND: The adverse effects of sepsis-associated acute kidney injury (SA-AKI) highlight the need for new biomarkers. Signal Peptide-Complement C1r/C1s, Uegf, Bmp1-Epidermal Growth Factor-like Domain-Containing Protein 2 (SCUBE2), important for angiogenesis and endothelial integrity, has been linked to increased mortality in models of lipopolysaccharide-induced lung injury. This research aimed to assess the utility of plasma SCUBE2 levels as a prognostic indicator for SA-AKI in intensive care unit (ICU) patients. METHODS: Between September 2020 and December 2022, our study enrolled ICU patients diagnosed with stage 3 SA-AKI. We collected demographic information, illness severity indices, and laboratory data, including plasma SCUBE2 and sepsis-triggered cytokine levels. We employed receiver operating characteristic curves and DeLong tests to assess the predictive accuracy for survival, Kaplan-Meier curves to evaluate the relative risk of death, and multivariate logistic regression to identify independent mortality predictors. RESULTS: Among the total of 200 participants, the survivors had significantly higher plasma SCUBE2 levels (115.9 ng/mL) compared to those who died (35.6 ng/mL). SCUBE2 levels showed a positive correlation with the anti-inflammatory cytokine IL-10 and a negative correlation with the APACHE II score, SOFA score, C-reactive protein, and monocyte chemoattractant protein-1. Multivariate analysis revealed that elevated SCUBE2 and IL-10 levels were independently protective against mortality, and associated with the most favorable 30-day survival outcomes. CONCLUSIONS: In ICU patients with stage 3 SA-AKI, lower plasma levels of SCUBE2 were correlated with elevated pro-inflammatory factors, which impacted survival outcomes. This suggests that SCUBE2 could be a potential biomarker for predicting prognosis in patients with SA-AKI.

Prediction of the risk of developing end-stage renal diseases in newly diagnosed type 2 diabetes mellitus using artificial intelligence algorithms.

OBJECTIVES: Type 2 diabetes mellitus (T2DM) imposes a great burden on healthcare systems, and these patients experience higher long-term risks for developing end-stage renal disease (ESRD). Managing diabetic nephropathy becomes more challenging when kidney function starts declining. Therefore, developing predictive models for the risk of developing ESRD in newly diagnosed T2DM patients may be helpful in clinical settings. METHODS: We established machine learning models constructed from a subset of clinical features collected from 53,477 newly diagnosed T2DM patients from January 2008 to December 2018 and then selected the best model. The cohort was divided, with 70% and 30% of patients randomly assigned to the training and testing sets, respectively. RESULTS: The discriminative ability of our machine learning models, including logistic regression, extra tree classifier, random forest, gradient boosting decision tree (GBDT), extreme gradient boosting (XGBoost), and light gradient boosting machine were evaluated across the cohort. XGBoost yielded the highest area under the receiver operating characteristic curve (AUC) of 0.953, followed by extra tree and GBDT, with AUC values of 0.952 and 0.938 on the testing dataset. The SHapley Additive explanation summary plot in the XGBoost model illustrated that the top five important features included baseline serum creatinine, mean serum creatine within 1 year before the diagnosis of T2DM, high-sensitivity C-reactive protein, spot urine protein-to-creatinine ratio and female gender. CONCLUSIONS: Because our machine learning prediction models were based on routinely collected clinical features, they can be used as risk assessment tools for developing ESRD. By identifying high-risk patients, intervention strategies may be provided at an early stage.

Survival benefit of a third dose of the COVID-19 vaccine among hemodialysis patients: A prospective cohort study.

BACKGROUND: Hemodialysis (HD) patients are particularly vulnerable to severe coronavirus disease 2019 (COVID-19) due to their immunocompromised state and comorbid conditions. Timely vaccination could be the most effective strategy to reduce morbidity and mortality. However, data on the survival benefit of the COVID-19 vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and death among HD patients are limited, especially during the Omicron-dominant period. METHODS: In this prospective hospital-based cohort study, we identified HD patients from July 1, 2021, to April 29, 2022. The patients were divided into fully vaccinated and partially vaccinated groups. We compared the humoral response, risk of developing SARS-CoV-2 infection, and all-cause mortality between the two groups. RESULTS: Among the 440 HD patients included, 152 patients were fully vaccinated, and 288 patients were partially vaccinated. Patients in the fully vaccinated group exhibited higher anti-spike protein receptor-binding domain (S protein RBD) antibody levels and lower risks of all-cause mortality (adjusted hazard ratio, 0.35; 95% confidence interval, 0.17-0.73; p = 0.005) than the partially vaccinated group. However, the risk for SARS-CoV-2 infection did not significantly differ between the two groups. Irrespective of the number of vaccinations, the risk of all-cause mortality was lower in patients with anti-S protein RBD antibody levels in the higher tertile. CONCLUSION: A third dose of the COVID-19 vaccine was associated with a decreased risk of all-cause mortality among HD patients during the Omicron-dominant period. A higher post-vaccination anti-S protein RBD antibody level was also associated with a lower risk of mortality.

Postdialysis blood pressure rise predicts long-term outcomes in chronic hemodialysis patients: a four-year prospective observational cohort study.

BACKGROUND: The blood pressure (BP) of a proportion of chronic hemodialysis (HD) patients rises after HD. We investigated the influence of postdialysis BP rise on long-term outcomes. METHODS: A total of 115 prevalent HD patients were enrolled. Because of the fluctuating nature of predialysis and postdialysis BP, systolic BP (SBP) and diastolic BP before and after HD were recorded from 25 consecutive HD sessions during a 2-month period. Patients were followed for 4 years or until death or withdrawal. RESULTS: Kaplan-Meier estimates revealed that patients with average postdialysis SBP rise of more than 5 mmHg were at the highest risk of both cardiovascular and all-cause mortality as compared to those with an average postdialysis SBP change between -5 to 5 mmHg and those with an average postdialysis SBP drop of more than 5 mmHg. Furthermore, multivariate Cox regression analysis indicated that both postdialysis SBP rise of more than 5 mmHg (HR, 3.925 [95% CI, 1.410-10.846], p = 0.008) and high cardiothoracic (CT) ratio of more than 50% (HR, 7.560 [95% CI, 2.048-27.912], p = 0.002) independently predicted all-cause mortality. We also found that patients with an average postdialysis SBP rise were associated with subclinical volume overload, as evidenced by the significantly higher CT ratio (p = 0.008). CONCLUSIONS: A postdialysis SBP rise in HD patients independently predicted 4-year cardiovascular and all-cause mortality. Considering postdialysis SBP rise was associated with higher CT ratio, intensive evaluation of cardiac and volume status should be performed in patients with postdialysis SBP rise.

Cardiovascular determinants of prognosis in normotensive hemodialysis patients.

BACKGROUND: Normotension has been hold to be the goal of hemodialysis. It remains obscure which cardiovascular parameter determines the prognosis in these normotensive hemodialysis patients. METHODS: We prospectively enrolled 145 hemodialysis patients, who had attained normotension without anti-hypertensive medications, and followed them for 72.6 ± 28.5 months. Important cardiovascular parameters were obtained at enrollment. Predictors for all-cause and cardiovascular mortalities were identified with the Cox model. RESULTS: There were 45 (18 cardiovascular/27 non-cardiovascular) deaths occurred during follow-up. Age, diabetes, left ventricular mass index (LVMI), left ventricular ejection fraction (LVEF), carotid intima-media thickness (CIMT), and aortic pulse wave velocity (PWV) were significant predictors for all-cause and cardiovascular mortalities. After adjustment for age and diabetes, only LVEF was significantly associated with all-cause mortality. LVEF was significantly associated with cardiovascular mortality. LVEF remained as a significant independent predictor of cardiovascular death after adjusting for age, diabetes, LVMI, CIMT, or PWV, respectively. CONCLUSION: LVEF is the independent predictor for all-cause and cardiovascular mortalities in the normotensive hemodialysis patients.

Artificial Intelligence for Risk Prediction of End-Stage Renal Disease in Sepsis Survivors with Chronic Kidney Disease.

Sepsis may lead to kidney function decline in patients with chronic kidney disease (CKD), and the deleterious effect may persist in patients who survive sepsis. We used a machine learning approach to predict the risk of end-stage renal disease (ESRD) in sepsis survivors. A total of 11,661 sepsis survivors were identified from a single-center database of 112,628 CKD patients between 2010 and 2018. During a median follow-up of 3.5 years, a total of 1366 (11.7%) sepsis survivors developed ESRD after hospital discharge. We adopted the random forest, extra trees, extreme gradient boosting, light gradient boosting machine (LGBM), and gradient boosting decision tree (GBDT) algorithms to predict the risk of ESRD development among these patients. GBDT yielded the highest area under the receiver operating characteristic curve of 0.879, followed by LGBM (0.868), and extra trees (0.865). The GBDT model revealed the strong effect of estimated glomerular filtration rates <25 mL/min/1.73 m2 at discharge in predicting ESRD development. In addition, hemoglobin and proteinuria were also essential predictors. Based on a large-scale dataset, we established a machine learning model computing the risk for ESRD occurrence among sepsis survivors with CKD. External validation is required to evaluate the generalizability of this model.

Urinary Galectin-3 as a Novel Biomarker for the Prediction of Renal Fibrosis and Kidney Disease Progression.

Plasma galectin-3 (Gal-3) is associated with organ fibrosis, but whether urinary Gal-3 is a potential biomarker of kidney disease progression has never been explored. Between 2018 and 2021, we prospectively enrolled 280 patients who underwent renal biopsy and were divided into three groups based on their urinary Gal-3 levels (<354.6, 354.6−510.7, and ≥510.8 pg/mL) to assess kidney disease progression (defined as ≥40% decline in the estimated glomerular filtration rate or end-stage renal disease) and renal histology findings. Patients in the highest urinary Gal-3 tertile had the lowest eGFRs and highest proteinuria levels. In multivariate Cox regression models, patients in the highest tertile had the highest risk of kidney disease progression (adjusted hazard ratio, 4.60; 95% confidence interval, 2.85−7.71) compared to those in the lowest tertile. Higher urinary Gal-3 levels were associated with more severe renal fibrosis. Intrarenal mRNA expression of LGALS3 (Gal-3-encoded gene) was most correlated with the renal stress biomarkers (IGFBP7 and TIMB2), renal function biomarkers (PTGDS) and fibrosis-associated genes (TGFB1). The urinary Gal-3 level may be useful for the identification of patients at high risk of kidney disease progression and renal fibrosis, and for the early initiation of treatments for these patients.

Echocardiographic features of left ventricular dysfunction and outcomes in chronic kidney disease.

OBJECTIVE: Heart failure (HF) imposes a substantial burden and the prevalence of HF is high in patients with chronic kidney disease (CKD). HF results in multiple hospital admissions, but whether HF subtypes worsen long-term outcomes and renal function in patients with CKD remains inconclusive. METHODS: The study comprised 10 904 patients with CKD aged ≥20 years who underwent echocardiography between 1 January 2011 and 31 December 2018. The patients were stratified into four groups: non-HF, HF with reduced ejection fraction (HFrEF), HF with mildly reduced ejection fraction (HFmrEF) and HF with preserved ejection fraction (HFpEF). The primary end points were all-cause mortality, major adverse cardiovascular events (MACEs) and adverse renal outcomes. RESULTS: In inverse probability of treatment weighting-adjusted method, the risk of all-cause mortality and MACEs relative to the non-HF group was greatest in the HFrEF group (HR 3.18 (95% CI 2.57 to 3.93) and HR 3.83 (95% CI 3.20 to 4.59)), followed by the HFmrEF (HR 2.75 (95% CI 2.22 to 3.42) and HR 3.08 (95% CI 2.57 to 3.69)) and HFpEF (HR 1.85 (95% CI 1.59 to 2.15) and HR 2.43 (95% CI 2.16 to 2.73) groups. In addition, the HFrEF group had the greatest risks of end-stage renal disease (HR 2.58 (95% CI 1.94 to 3.44)) compared with other groups. CONCLUSIONS: HF is associated with subsequent worse clinical outcomes, which may be more pronounced in patients with HFrEF, followed by those with HFmrEF and those with HFpEF relative to non-HF group.

Dose-response effects of physical activity on all-cause mortality and major cardiorenal outcomes in chronic kidney disease.

AIMS: Physical activity has a protective effect against mortality and cardiovascular events in chronic kidney disease (CKD) patients. Nonetheless, how different levels of physical activity affect the health benefits in CKD remains unclear. This study aimed to investigate the dose-response effects of physical activity on mortality and major cardiorenal events in CKD. METHODS AND RESULTS: We evaluated a longitudinal cohort of 4508 Taiwanese CKD patients between 2004 and 2017. Physical activity was assessed by the NHANES questionnaire and quantified in metabolic equivalent-hours per week (MET-hour/week). Patients were categorized into highly active (≥7.5 MET-h/week), low-active (0.1 to <7.5 MET-h/week), or inactive (0 MET-h/week) groups. Cox regression and restricted cubic spline models were utilized to explore the association between physical activity and the risks of study outcomes, including all-cause mortality, end-stage renal disease (ESRD), and major adverse cardiovascular events (MACE, a composite of cardiovascular death, myocardial infarction, ischaemic stroke, and hospitalized heart failure). During a median follow-up of 686 days, 739 death, 1059 ESRD, and 521 MACE events occurred. Highly active group had the lowest chance of all study outcomes, followed by low-active and inactive groups (P < 0.001). Multivariable Cox regression showed that only highly active group was independently associated with lower risks for all-cause mortality [hazard ratio (HR) 0.62; 95% confidence interval (CI) 0.53-0.74], ESRD (HR 0.83, 95% CI 0.72-0.96), and MACE (HR 0.63, 95% CI 0.51-0.76) compared to the inactive group. The risks of MACE did not further decrease once physical activity surpassed 15 MET-h/week, indicating a U-shaped association. The results were consistent in the subgroup and sensitivity analyses. CONCLUSION: Physical activity of 7.5 to <15 MET-h/week is associated with lower risks of adverse cardiorenal outcomes and should be integrated into the care of CKD.

Antithrombotic Therapy for Chronic Kidney Disease Patients With Concomitant Atrial Fibrillation and Coronary Artery Disease.

Background: Oral anticoagulants (OAC) plus antiplatelets is recommended for patients with atrial fibrillation (AF) and coronary artery disease (CAD) to reduce thromboembolism. However, there is limited evidence regarding antithrombotic therapy for patients with concomitant chronic kidney disease (CKD), AF, and CAD, especially those not undergoing percutaneous coronary intervention. We aimed to use real-world data assessing the efficacy and safety of antithrombotic regimens in this population. Methods: We used a single-center database of 142,624 CKD patients to identify those receiving antithrombotic therapy for AF and CAD between 2010 and 2018. Patients taking warfarin or direct OAC (DOAC) alone were grouped in the OAC monotherapy (n = 537), whereas those taking OAC plus antiplatelets were grouped in the combination therapy (n = 2,391). We conducted propensity score matching to balance baseline covariates. The endpoints were all-cause mortality, major adverse cardiovascular events, and major bleedings. Results: After 1:4 matching, the number of patients in OAC monotherapy and combination therapy were 413 and 1,652, respectively. Between the two groups, combination therapy was associated with higher risks for ischemic stroke (HR 2.37, CI 1.72-3.27), acute myocardial infarction (HR 6.14, CI 2.51-15.0), and hemorrhagic stroke (HR 3.57, CI 1.35-9.81). The results were consistent across CKD stages. In monotherapy, DOAC users were associated with lower risks for all-cause mortality, AMI, and gastrointestinal bleeding than warfarin, but the stroke risk was similar between the two subgroups. Conclusions: For patients with concomitant CKD, AF and CAD not undergoing PCI, OAC monotherapy may reduce stroke and AMI risks. DOAC showed more favorable outcomes than warfarin.

AN69 Filter Membranes with High Ultrafiltration Rates during Continuous Venovenous Hemofiltration Reduce Mortality in Patients with Sepsis-Induced Multiorgan Dysfunction Syndrome.

Polyacrylonitrile (AN69) filter membranes adsorb cytokines during continuous venovenous hemofiltration (CVVH). Although high-volume hemofiltration has shown limited benefits, the dose-effect relationship in CVVH with AN69 membranes on severe sepsis remains undetermined. This multi-centered study enrolled 266 patients with sepsis-induced multiorgan dysfunction syndrome (MODS) who underwent CVVH with AN69 membranes between 2014 and 2015. We investigated the effects of ultrafiltration rates (UFR) on mortality. We categorized patients that were treated with UFR of 20-25 mL/kg/h as the standard UFR group (n = 124) and those that were treated with a UFR >25 mL/kg/h as the high UFR group (n = 142). Among the patient characteristics, the baseline estimated glomerular filtration rates (eGFR) <60 mL/min/1.73 m2, hemoglobin levels <10 g/dL, and a sequential organ failure assessment (SOFA) score ≥15 at CVVH initiation were independently associated with in-hospital mortality. In the subgroup analysis, for patients with SOFA scores that were ≥15, the 90-day survival rate was higher in the high UFR group than in the standard UFR group (HR 0.54, CI: 0.36-0.79, p = 0.005). We concluded that in patients with sepsis-induced MODS, SOFA scores ≥15 predicted a poor rate of survival. High UFR setting >25 mL/kg/h in CVVH with AN69 membranes may reduce the mortality risk in these high-risk patients.

Identification of Galectin-3 as Potential Biomarkers for Renal Fibrosis by RNA-Sequencing and Clinicopathologic Findings of Kidney Biopsy.

Background: Galectin-3 (Gal-3) is a multifunctional glycan-binding protein shown to be linked to chronic inflammation and fibrogenesis. Plasma Gal-3 is associated with proteinuria and renal dysfunction, but its role has never been confirmed with kidney biopsy results. In our study, we aimed to explore the expression of Gal-3 in biopsy-proven patients, and we tested the hypothesis that chronic kidney disease (CKD) leads to upregulation of plasma Gal-3 expression in corresponding biopsy findings and RNA sequencing analysis. Method: In 249 patients (male/female: 155/94, age: 57.2 ± 16.3 years) who underwent kidney biopsy, plasma levels of Gal-3 were measured to estimate the association of renal fibrosis. Relationships between plasma Gal-3 levels, estimated glomerular filtration rate (eGFR) and renal histology findings were also assessed. We further examined the gene expression of Gal-3 in RNA-sequencing analysis in biopsy-proven patients. Results: Compared to patients without CKD, CKD patients had higher levels of plasma Gal-3 (1,016.3 ± 628.1 pg/mL vs. 811.6 ± 369.6 pg/ml; P = 0.010). Plasma Gal-3 was inversely correlated with eGFR (P = 0.005) but not with proteinuria. Higher Gal-3 levels were associated with interstitial fibrosis, tubular atrophy and vascular intimal fibrosis. RNA-sequencing analysis showed the upregulation of Gal-3 in fibrotic kidney biopsy samples, and the differentially expressed genes were mainly enhanced in immune cell activation and the regulation of cell-cell adhesion. Conclusions: Plasma Gal-3 levels are inverse correlated with eGFR but positively correlated with renal fibrosis, which may be involved in the immune response and associated pathways. These findings support the role of Gal-3 as a predictive marker of renal fibrosis.

Comparative proteomic analysis of rat aorta in a subtotal nephrectomy model.

Although accelerated atherosclerosis and arteriosclerosis are the main causes of cardiovascular morbidity and mortality in chronic kidney disease (CKD) patients, the molecular pathogenesis remains largely obscure. Our study of the aortic function in a typical CKD model of subtotal nephrectomy (SNX) rats demonstrated phenotypes that resemble CKD patients with aortic stiffness. The 2-DE analysis of rat aortas followed by MS identified 29 up-regulated and 53 down-regulated proteins in SNX rats. Further Western blot and immunohistochemistry analyses validated the decreased HSP27 and increased milk fat globule epidermal growth factor-8 (MFG-E8) in SNX rats. Functional classification of differential protein profiles using KOGnitor revealed that the two major categories involved in aortic stiffness are posttranslational modification, protein turnover, chaperones (23%) and cytoskeleton (21%). Ingenuity Pathway Analysis highlighted cellular assembly and organization, and cardiovascular system development and function as the two most relevant pathways. Among the identified proteins, the clinical significance of the secreted protein MFG-E8 was confirmed in 50 CKD patients, showing that increased serum MFG-E8 level is positively related to aortic stiffness and renal function impairment. Drug interventions with an inhibitor of the angiotensin converting enzyme, enalapril, in SNX rats improved aortic stiffness and decreased MFG-E8 depositions. Together, our studies provide a repertoire of potential biomarkers related to the aortic stiffness in CKD.

The Anastomotic Angle of Hemodialysis Arteriovenous Fistula Is Associated With Flow Disturbance at the Venous Stenosis Location on Angiography.

The juxta-anastomotic stenosis of an arteriovenous fistula (AVF) is a significant clinical problem in hemodialysis patients with no effective treatment. Previous studies of AV anastomotic angles on hemodynamics and vascular wall injury were based on computational fluid dynamics (CFD) simulations using standardized AVF geometry, not the real-world patient images. The present study is the first CFD study to use angiographic images with patient-specific outcome information, i.e., the exact location of the AVF stenotic lesion. We conducted the CFD analysis utilizing patient-specific AVF geometric models to investigate hemodynamic parameters at different locations of an AVF, and the association between hemodynamic parameters and the anastomotic angle, particularly at the stenotic location. We analyzed 27 patients who used radio-cephalic AVF for hemodialysis and received an angiographic examination for juxta-anastomotic stenosis. The three-dimensional geometrical model of each patient's AVF was built using the angiographic images, in which the shape and the anastomotic angle of the AVF were depicted. CFD simulations of AVF hemodynamics were conducted to obtain blood flow parameters at different locations of an AVF. We found that at the location of the stenotic lesion, the AV angle was significantly correlated with access flow disturbance (r = 0.739; p < 0.001) and flow velocity (r = 0.563; p = 0.002). Furthermore, the receiver operating characteristic (ROC) curve analysis revealed that the AV angle determines the lesion's flow disturbance with a high area under the curve value of 0.878. The ROC analysis also identified a cut-off value of the AV angle as 46.5°, above or below which the access flow disturbance was significantly different. By applying CFD analysis to real-world patient images, the present study provides evidence that an anastomotic angle wider than 46.5° might lead to disturbed flow generation, demonstrating a reference angle to adopt during the anastomosis surgery.

Tissue Doppler imaging predicts outcomes in hemodialysis patients with preserved left ventricular function.

BACKGROUND: Cardiovascular disease is a major cause of mortality in patients with end-stage renal disease (ESRD). In addition to arteriosclerosis (arterial stiffness) and atherosclerosis, left ventricular (LV) hypertrophy and LV systolic dysfunction are the major cardiac determinants of cardiovascular mortality in hemodialysis patients. Although LV diastolic dysfunction is common in patients with ESRD, its prognostic value is yet to be established. METHODS: A total of 103 ESRD patients (52 females, 51 males, age 51 ± 14 years) receiving regular hemodialysis and with preserved LV systolic function were prospectively enrolled in the current study. A comprehensive cardiovascular evaluation was performed at baseline. LV diastolic function was assessed using Doppler mitral inflow velocity and tissue Doppler imaging (TDI) of the mitral annulus velocity. Predictors for hospitalization and all-cause mortality were identified via Cox proportional hazards analysis. RESULTS: There were 20 deaths and 46 hospitalizations during a follow-up period of 67.9 ± 20.2 months. After adjusting for age, aortic pulse wave velocity (PWV), and carotid intima media thickness, Cox analysis demonstrated that ratio of early ventricular filling velocity (E) to early diastolic tissue velocity mitral annulus (E') (E/E') was a significant predictor for hospitalization (hazard ratio [HR] 1.235 and 95% CI 1.115-1.368 per-1SD). E' also independently predicted mortality (HR 0.682, 95% CI 0.472-0.985). The TDI parameters significantly correlated with the LV mass index and PWV. CONCLUSION: The findings of the current study suggest that diastolic function, as indexed by TDI, is an independent predictor of hospitalization and mortality in ESRD patients receiving regular hemodialysis and with preserved LV systolic function. The TDI parameters may reflect the impairment of arterial function and LV pressure overload.

Increased Nighttime Pulse Pressure Variability but Not Ambulatory Blood Pressure Levels Predicts 14-Year All-Cause Mortality in Patients on Hemodialysis.

Increased short-term blood pressure (BP) variability is associated with adverse cardiovascular outcomes in patients with hypertension. The present study investigated the long-term prognostic significance of the short-term blood pressure variability in patients on hemodialysis. A total of 149 patients (53.0% male; mean age: 54.5±15.1 years) receiving regular hemodialysis for >6 months were enrolled. They completed a 44-hour (excluding the hemodialysis session) ambulatory BP monitoring and comprehensive hemodynamic assessments, including carotid-femoral pulse wave velocity and pressure waveform decomposition (forward and backward wave amplitude). Blood pressure variability parameters, including average real variability (ARV) of systolic BP, diastolic BP, and pulse pressure (ARVp) during daytime, nighttime, and overall 44 hours were calculated. During a median follow-up of 14 years, 78 deaths (52.4%) were confirmed. In multivariable Cox regression analysis, none of the ambulatory BP parameters were predictive of mortality. In contrast, nighttime ARVp was consistently and significantly associated with all-cause mortality in multivariable Cox models adjusting for age, sex, albumin, hemodialysis treatment adequacy, and 44-hour systolic BP (continuous variable analysis, per 1-SD, hazard ratio=1.348; 95% CI, 1.029-1.767; categorical variable analysis, ≥8.5 versus <8.5 mm Hg; hazard ratio=1.825; 95% CI, 1.074-3.103). Forward wave amplitude and 44-hour systolic BP were identified as the 2 most important determinants of nighttime ARVp. Addition of nighttime ARVp to the base model significantly improved prediction of all-cause mortality (Net reclassification improvement =0.198; P=0.0012). In hemodialysis patients, increased short-term nighttime pulse pressure variability but not ambulatory BP levels were significantly predictive of long-term all-cause mortality.