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ObjectiveHeart 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.MethodsThe 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.ResultsIn 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.ConclusionsHF 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.

Context.— Galectin-9 reduces tissue damage in certain immune-mediated glomerular diseases. However, its role in structural and functional renal changes in patients with varying types of chronic kidney disease (CKD) is less clear. Objective.— To investigate the association between plasma galectin-9 levels, proteinuria, tubulointerstitial lesions, and renal function in different CKD stages. Design.— We measured plasma galectin-9 levels in 243 patients undergoing renal biopsy for determining the CKD etiology. mRNA and protein expression levels of intrarenal galectin-9 were assessed by quantitative real-time polymerase chain reaction and immunostaining. Relationships between plasma galectin-9, clinical characteristics, and tubulointerstitial damage were analyzed with logistic regression. We investigated galectin-9 expression patterns in vitro in murine J774 macrophages treated with differing stimuli. Results.— To analyze the relationship between galectin-9 and clinical features, we divided the patients into 2 groups according to median plasma galectin-9 levels. The high galectin-9 group tended to be older and to have decreased renal function, higher proteinuria, and greater interstitial fibrosis. After multivariable adjustment, elevated plasma galectin-9 levels were independently associated with stage 3b or higher CKD. An analysis of gene expression in the tubulointerstitial compartment in the biopsy samples showed a significant positive correlation between intrarenal galectin-9 mRNA expression and plasma galectin-9 levels. Immunohistochemistry confirmed increased galectin-9 expression in the renal interstitium of patients with advanced CKD, and most galectin-9–positive cells were macrophages, as determined by double-immunofluorescence staining. In vitro experiments showed that galectin-9 expression in macrophages was significantly increased after interferon-γ stimulation. Conclusions.— Our findings suggest that plasma galectin-9 is a good biomarker for diagnosing advanced CKD.

Chronic kidney disease (CKD) is a global public health issue. CKD is caused by the infiltration of various myeloid cell types into renal tissue, resulting in renal fibrosis and tubular atrophy. Unilateral ureteral obstruction (UUO) surgery in mice is a model of CKD and characterized by high expression of the anti-inflammatory receptor, Triggering receptor expressed on myeloid cells 2 (TREM-2), on myeloid cells in affected kidneys. Here, we show that iNOS expression and nitric oxide (NO) induction were decreased in Trem-2

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.

The 2019 Kidney Disease Outcome Quality Initiative (K/DOQI) guideline recommended evaluating arteriovenous fistula (AVF) malfunction risks primarily based on clinical monitoring, which can be assisted with the value of vascular access flow (Qa). Nevertheless, Qa thresholds recommended by different guidelines vary, ranging from 300 to 500 ml/min. This study investigated the optimal Qa threshold to predict future functional patency in AVFs with Qa 500 ml/min.Both the clinical indicators of access dysfunction and the Qa value were monitored in patients receiving hemodialysis by the radiocephalic AVF. Routine access flow surveillance was performed by the ultrasound dilution method (HD03, Transonic Inc.). The development of clinically significant indicators of access dysfunction, which necessitated percutaneous transluminal angiography (PTA) to maintain functional patency, was analyzed in this cohort.Among the enrolled 302 patients, Qa of 52 patients was under 500 ml/min. These 52 patients received 2 Qa measurements during the follow-up period. Of these 52 patients, serial Qa of 17 patients varied trivially and their AVF remained functional. Multivariable logistic regression analysis revealed that a low Qa per ideal body weight (IBW) is an independent predictor of AVF functional loss. Receiver operating characteristic curve analysis of Qa/IBW in predicting future AVF functional loss revealed that the best cutoff value of Qa is 7.1 times the IBW.For radiocephalic AVFs with Qa 500 ml/min, the minimally required Qa to maintain access function is associated with individual IBW. The IBW-based Qa threshold assessment would allow more flexibility in the treatment of patients and reduce unnecessary invasive measures.

End-stage kidney disease (ESKD) is a global burden that reflects each country's unique condition. We used the National Health Insurance Research Database (NHIRD) of Taiwan to decipher changes in the mortality and international survival rates and to determine the effectiveness of the pre-end-stage renal disease care program (pre-ESRD care program) to guide future health policies for ESKD.We conducted a retrospective cohort analysis of the NHIRD data along with records from the catastrophic illness certificate program of ESKD patients from 2010 to 2018.From 2010 to 2018, the annual dialysis-related mortality rate in Taiwan increased from 10.6 to 11.8 deaths per hundred patient-years. The mortality rate for patients below 40 years appears to be decreasing, reflecting the improved quality of care for ESKD patients. Patients above 75 years showed increasing mortality, indicating the prolonged survival and aging of the ESKD population. Patients undergoing dialysis who participated in the pre-ESRD care program had a higher post-dialysis initiation life expectancy than those who did not participate. Among the program enrollees, the post-dialysis initiation life expectancy was higher in patients who had participated for more than one year. Taiwan has one of the highest ESKD patient survival rates globally.From 2010 to 2018, the reduced mortality in young patients and aging of the ESKD population might indicate that the quality of care in Taiwan for ESKD has improved. Furthermore, a better survival rate after dialysis initiation was observed in the pre-ESRD care program participants.

Introduction: Viable vascular access is the lifeline for hemodialysis patients. In the nondialysis population, emerging evidence suggests that circulating pentraxin 3 (PTX3), neutrophil gelatinase-associated lipocalin (NGAL), and chitinase-3-like protein 1 (CHI3L1) are associated with cardiovascular inflammation and endothelial injury. However, predictive values of these three biomarkers on arteriovenous fistula (AVF) outcomes are unknown. Methods: This prospective observational cohort study enrolled 135 hemodialysis patients using AVF and then followed them for 3 years. Plasma levels of PTX3, NGAL, and CHI3L1 were measured. Patients were followed up prospectively for two clinical outcomes, including AVF functional patency loss and death. Cox proportional hazards regression models were used to analyze hazard ratios for the commencement of AVF functional patency loss and mortality. Results: Among 135 patients, the mean age was 66.0 ± 15.7 years old and 48.1% were male. The plasma level of PTX3, NGAL, and CHI3L1 was 2.8 ± 2.3 ng/mL, 349.2 ± 111.4 ng/mL, and 185.5 ± 66.8 ng/mL, respectively. During a 3-year follow-up period, the plasma level of PTX3 was an independent predictor for AVF functional patency loss (per 1 ng/mL increase, HR 1.112 [95% CI: 1.001–1.235], p = 0.048). Besides, patients with higher plasma levels of PTX3 were more likely to suffer from cardiovascular mortality (per 1 ng/mL increase, HR 1.320 [95% CI: 1.023–1.703], p = 0.033), infectious mortality (per 1 ng/mL increase, HR 1.394 [95% CI: 1.099–1.769], p = 0.006), and all-cause mortality (per 1 ng/mL increase, HR 1.233 [95% CI: 1.031–1.476], p = 0.022). Conclusions: The plasma level of PTX3, not NGAL or CHI3L1, was associated with higher risks of AVF functional patency loss in chronic hemodialysis patients, showing its value in reflecting AVF endothelial dysfunction. Furthermore, PTX3 also predicts mortality in chronic hemodialysis patients.

Chronic kidney disease (CKD)-associated mental disorders have been attributed to the excessive accumulation of hemodialysis-resistant indoxyl-3-sulfate (I3S) in the brain. I3S not only induces oxidative stress but is also a potent endogenous agonist of the aryl hydrocarbon receptor (AhR). Here, we investigated the role of AhR in CKD-induced brain disorders using a 5/6 nephrectomy-induced CKD mouse model, which showed increased I3S concentration in both blood and brain, anxiety and impaired novelty recognition, and AhR activation in the anterior cortex. GFAP

BackgroundChronic kidney disease (CKD) is known to increase the risk of atrial fibrillation (AF) development, but the relationship between AF and subsequent renal function decline in patients with CKD is not well understood. In this study, we explored the role of AF on renal outcomes among patients with CKD.MethodsIn a retrospective hospital-based cohort study, we identified patients with CKD aged ≥20 years from 1 January 2008 to 31 December 2018. The patients were divided into AF and non-AF groups. We matched each patient with CKD and AF to two non-AF CKD controls according to propensity scores. The outcomes of interest included estimated glomerular filtration rate (eGFR) decline of ≥20%, ≥30%, ≥40% and ≥50%, and end-stage renal disease (ESRD).ResultsAfter propensity score matching, 6731 patients with AF and 13 462 matched controls were included in the analyses. Compared with the non-AF group, the AF group exhibited greater risks of eGFR decline ≥20% (HR 1.43; 95% CI 1.33 to 1.53), ≥30% (HR 1.50; 95% CI 1.36 to 1.66), ≥40% (HR 1.62; 95% CI 1.41 to 1.85) and ≥50% (HR 1.82; 95% CI 1.50 to 2.20), and ESRD (HR 1.22; 95% CI 1.12 to 1.34). Higher CHA2DS2-VASc scores were associated with greater risks of eGFR decline and ESRD.ConclusionsIn patients with CKD, AF was associated with greater risks of subsequent renal function decline. CHA2DS2-VASc scores may be a useful risk stratification scheme for predicting the risk of renal function decline.

BackgroundDecoy receptor 3 (DcR3) belongs to the tumor necrosis factor (TNF) receptor superfamily and neutralizes TNF ligands, including FasL and TRAIL, to prevent T activation during T-cell priming. However, the cellular mechanisms underlying acute cell-mediated rejection (ACMR) remain unknown.MethodsWe generated DcR3 transgenic (Tg) mice and mice with high DcR3 expression (HDE) to study both in vivo and in vitro. FasR RNA knockdown in immortalized CD4+CD8+ T-cells was used to survey the role of DcR3 on FasR/Fas-associated protein with death domain (FADD)/caspase 8 pathway and its cross-link to TNF receptor-associated factor 1 (TNFR1)-associated death domain protein (TRADD) in suppressing TNFR1. TNF/TRADD knockout mice were used to show the importance of TNF adaptor protein.ResultsDcR3.Fc suppressed C57BL/6 female T-cell activation and transformation into CD4+CD69+, CD4+CD44+, and CD4+CD25+Foxp3+ when compared with isotype IgG1 and its co-treatment with FasL/TRAIL after exposing to bone marrow-derived dendritic cells (BMDCs) that carried alloantigen with male H-Y and minor antigenic determinant. Interleukin-17 and interferon-γ productions by BMDC-activated T-cells were lowered after co-treating with DcR3.Fc. DcR3.Fc induced effector T-cells (Teffs) and was susceptible to FasR-mediated apoptosis through the FADD/TRADD/caspase 8 pathway. After exposing to DcR3.Fc, TRADD was silenced, likely turning down the inflammatory response. The systemic effects of DcR3 Tg mice and HDE phenotype induced by the promoter of cytomegalovirus not only attenuated ACMR severity but also ameliorated the high serum creatinine and blood urea nitrogen levels even with high T-cell exposure frequencies. Besides this, DcR3 has minor biological effects on both MHC-matched and MHC-mismatched models.ConclusionsHigh DcR3 doses protect renal tubular epithelial cells from acute T-cell attack during the T-cell priming stage via interfering with TNF ligand-mediated reverse signaling and possibly promoting Teff apoptosis through FasR upregulation. Our findings supported that the decoy receptor is involved in T-cell modulation in kidney transplant rejection.

Background A discordant biological clock could potentially induce sudden cardiac death (SCD). We aimed to evaluate the circadian change of heart rate variability (HRV) and its relationship to the risks of ventricular arrhythmia (VA) and near syncope in patients with chronic kidney disease (CKD). Methods In this retrospective study, non-CKD and CKD patients were enrolled and underwent a 24-hour Holter examination for linear and nonlinear HRV analyses. The multiscale entropy (MSE) method was selected for nonlinear HRV analyses. The documented VAs or episodes of near syncope were classified as high-risk SCD group (n = 8) and others as low-risk SCD group (n = 21). Results In linear analyses, time and frequency domains revealed no significant difference between groups. In nonlinear analyses with MSE, MSE5, MSE6–20, and MSEslope 5 were significantly lower (p = 0.002, p Conclusions Nonlinear analysis with MSE demonstrated the loss of circadian change in CKD patients and was associated with a higher risk for VAs and near syncope. The MSE method demonstrated the diurnal change of rhythm dynamics which identifies potential autonomic dysfunction leading to poor prognosis.

The peritoneal equilibration test (PET) is a semi-quantitative measurement that characterizes the rate of transfer of solutes and the water transfer rate across the peritoneum in patients treated with peritoneal dialysis (PD). The results of the PET are used to maximize daily peritoneal ultrafiltration and solute clearances. Previous studies have shown that high transport status is associated with ultrafiltration failure, malnutrition, and reduced survival; however, the way in which peritoneum transport characteristics affect peritonitis risk is unknown. In the current cohort study, we recruited 898 incident-PD patients and used intention-to-treat analysis to test if baseline PET affected the subsequent 3-year peritonitis rate. Among all recruited PD patients, 308 (34.2%) developed peritonitis within three years. Multivariate Cox regression analysis showed that the high-transport group has the greatest peritonitis risk (HR 1.98, 95% CI: 1.08–3.62) even after an adjustment for demographics, comorbid diseases, and biochemical measurements. We concluded that a baseline high peritoneal membrane transport rate is an independent risk factor for peritonitis in incident PD patients.

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 (

ObjectivesMaintenance of vascular access (VA) patency after percutaneous transluminal angioplasty (PTA) is important and remains a challenge despite VA monitoring and surveillance. The aim of this study was to examine factors affecting the post-PTA arteriovenous access (AVA) patency in patients who have been on close VA monitoring and surveillance for access flow.DesignRetrospective cohort study.SettingA single medical centre in Taiwan.ParticipantsRecords of patients who received chronic haemodialysis between 1 January 2017 and 31 December 2018 were retrospectively reviewed. Patients were divided into two groups (without or with PTA intervention on AVA).Primary and secondary outcomePatients were followed until reintervention PTA, termination or abandoned VA or end of study. In addition to routine monitoring, VA flow surveillance was performed every 3 months for detection of VA dysfunction adhering to Kidney Disease Outcomes Quality Initiative guidelines.ResultsA total of 508 patients were selected for study inclusion (with PTA, n=231; without PTA, n=277). At baseline, variables that differed between groups included malignancy and levels of albumin, uric acid, potassium, phosphorous, high-density lipoprotein, total bilirubin and ferritin (all pConclusionsAVG access type, acute myocardial infarction, and high ferritin levels are risk factors for re-intervention post-PTA. These findings may be useful in the development of prophylactic strategies for monitoring VA function and tailoring surveillance programs for these dialysis patients.

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.

Transcriptional co-activator with PDZ-binding motif (TAZ) is a key downstream effector of the Hippo tumor-suppressor pathway. The functions of TAZ in the kidney, especially in tubular epithelial cells, are not well-known. To elucidate the adaptive expression, protective effects on kidney injury, and signaling pathways of TAZ in response to acute kidney injury (AKI), we used in vitro (hypoxia-treated human renal proximal tubular epithelial cells [RPTECs]) and in vivo (mouse ischemia–reperfusion injury [IRI]) models of ischemic AKI. After ischemic AKI, TAZ was up-regulated in RPTECs and the renal cortex or tubules. Up-regulation of TAZ in RPTECs subjected to hypoxia was controlled by IκB kinase (IKK)/nuclear factor κ-light-chain-enhancer of activated B cell (NF-κB) signaling. TAZ overexpression attenuated hypoxic and oxidative injury, inhibited apoptosis and activation of p38 and c-Jun N-terminal kinase (JNK) proteins, and promoted wound healing in an RPTEC monolayer. However, TAZ knockdown aggravated hypoxic injury, apoptosis, and activation of p38 and JNK signaling, delayed wound closure of an RPTEC monolayer, and promoted G0/G1 phase cell-cycle arrest. Chloroquine and verteporfin treatment produced similar results to TAZ overexpression and knockdown in RPTECs, respectively. Compared with vehicle-treated mice, chloroquine treatment increased TAZ in the renal cortex and tubules, improved renal function, and attenuated tubular injury and tubular apoptosis after renal IRI, whereas TAZ siRNA and verteporfin decreased TAZ in the renal cortex and tubules, deteriorated renal failure and tubular injury, and aggravated tubular apoptosis. Our findings indicate the renoprotective role of tubular TAZ in ischemic AKI. Drugs augmenting (e.g., chloroquine) or suppressing (e.g., verteporfin) TAZ in the kidney might be beneficial or deleterious to patients with AKI.

A novel infectious disease, coronavirus disease-2019 (COVID-19), spread globally since December 2019. Without effective treatment and vaccination, the strategies to restrain this disease are only keeping social distance, maintaining personal hygiene, quarantine, and isolation. However, thrice-a-week treatment is inevitable for all hemodialysis patients. In addition to the high risk of cluster infection and compromised immunity in patients with end-stage renal disease (ESRD), an atypical disease presentation could also make the medial system neglect these patients during CVOID-19 pandemic. To avoid COVID-19 transmission among patients on dialysis, the major societies of nephrology around the world have provided their guidelines for screening, dialysis facilities adjustment, and health education, respectively. In this review, we summarized the main contents and differences of these guidelines and addressed the prompt management for patients with ESRD to reduce the risk of infection during COVID-19 pandemic.

Anemia is the major complication resulting from chronic kidney disease (CKD) and also a risk factor for cardiovascular events and a poor quality of life (QoL). Diabetic kidney disease (DKD) is the major cause of CKD. Initially, insulin resistance has been reported to increase erythropoiesis, but it might be a minor issue. DKD-related anemia developed earlier and was more severe than non-DKD-related anemia based on more complicated mechanisms, including greater bleeding tendency associated with antiplatelet effect, less O2 sensing due to autonomic neuropathy or renin-angiotensin-aldosterone system inhibitor use, inhibitory effect of inflammatory cytokines, urinary loss of erythropoietin (EPO), and poor response to EPO. In DKD patients, prompt correction of anemia allows for a better cardiovascular outcome and QoL, which are similar to the promising effect of anemia correction in CKD patients. However, current evidence recommended that the avoidance of a high or normalized hemoglobin (Hb) level has been suggested in the treatment of anemia in DKD patients. Despite that EPO has a pleotropic effect on renal protection from animal studies, the renal benefit was less evident in CKD and DKD patients. Recently, the antidiabetic agent, sodium glucose cotransporter-2 inhibitors (SGLT2i), has been reported to exhibit the renal benefits due to the tubulo-glomerular feedback in addition to sugar control. It may also be due to less renal ischemic through higher EPO levels, followed by higher Hb levels. More studies are needed to clarify the link between the renal benefit of SGLT2i and EPO production.

An anti-cytomegalovirus (CMV) immunoglobulin G (IgG) antibody is produced after primary CMV infection and generally persists after the primary infection. However, it is not well-known about the relationship between anti-CMV IgG titer and outcomes in kidney transplant recipients. We, therefore, aimed to explore the role of anti-CMV IgG titer on the risks of CMV disease development, allograft rejection, renal function decline, and mortality.In a hospital-based study, we identified 179 CMV-seropositive kidney transplant recipients between January 2013 and December 2017. These patients were divided into low and high anti-CMV IgG titer groups, respectively. The cutoff level of anti-CMV IgG titer was determined by receiver operating characteristic curve analysis. The outcomes evaluated included CMV disease, decrease of ≥15% in estimated glomerular filtration rate (eGFR), biopsy-proven allograft rejection, and all-cause mortality.The high anti-CMV IgG titer group (≥846.2 AU/mL) exhibited a higher risk of CMV disease (adjusted hazard ratio [aHR], 3.77; 95% CI, 1.47-9.68; p = 0.006), eGFR decline ≥15% (aHR, 2.00; 95% CI, 1.19-3.35; p = 0.009), and renal allograft rejection (aHR, 2.95; 95% CI, 1.11-7.87; p = 0.030) than the low titer group (846.2 AU/mL).In kidney transplant recipients, a high anti-CMV IgG titer was associated with higher risks for developing CMV disease, undergoing allograft rejection, and eGFR decline.

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.

Arteriovenous fistula (AVF) is the vascular access of choice for renal replacement therapy. However, AVF is susceptible to calcification with a high prevalence of 40%-65% in chronic hemodialysis patients. Repeated needle puncture for hemodialysis cannulation results in intimal denudation of AVF. We hypothesized that exposure to blood shear stress in the medial layer promotes venous smooth muscle cell (SMC) osteogenesis. While previous studies of shear stress focused on arterial-type SMCs, SMCs isolated from the vein had not been investigated. This study established a venous cell model of AVF using the fluid shear device, combined with a high phosphate medium to mimic the uremic milieu. Osteogenic gene expression of venous SMCs upon mechanical and chemical cues was analyzed in addition to the activated cell signaling pathways. Our findings indicated that upon shear stress and high phosphate environment, mechanical stimulation (shear stress) had an additive effect in up-regulation of an early osteogenic marker, Runx2. We further identified that the integrin β1-ERK1/2 signaling pathway was responsible for the molecular basis of venous SMC osteogenesis upon shear stress exposure. Mitochondrial biogenesis also took part in the early stage of this venopathy pathogenesis, evident by the up-regulated mitochondrial transcription factor A and mitochondrial DNA polymerase γ in venous SMCs. In conclusion, synergistic effects of fluid shear stress and high phosphate induce venous SMC osteogenesis via the ERK1/2 pathway through activating the mechanosensing integrin β1 signaling. The present study identified a promising druggable target for reducing AVF calcification, which deserves further in vivo investigations.

BackgroundSepsis is known to cause renal function fluctuations during hospitalization, but whether these patients discharged from sepsis were still at greater risks of long-term renal adverse outcomes remains unknown.MethodsFrom 2011 to 2018, we included 1,12,628 patients with chronic kidney disease (CKD) aged ≥ 20 years. The patients with CKD were further divided into 11,661 sepsis group and 1,00,967 non-sepsis group. The following outcome of interest was included: all-cause mortality, readmission for acute kidney injury, estimated glomerular filtration rate decline ≥50% or doubling of serum creatinine, and end-stage renal disease.ResultsAfter propensity score matching, the sepsis group was at higher risks of all-cause mortality [hazard ratio (HR) 1.39, 95% CI, 1.31–1.47], readmission for acute kidney injury (HR 1.67, 95% CI 1.58–1.76), eGFR decline ≥ 50% or doubling of serum creatinine (HR 3.34, 95% CI 2.78–4.01), and end-stage renal disease (HR 1.43, 95% CI 1.34–1.53) than non-sepsis group.ConclusionsOur study found that patients with CKD discharged from hospitalization for sepsis have higher risks of subsequent renal adverse events.

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 &gt, 25 mL/kg/h as the high UFR group (n = 142). Among the patient characteristics, the baseline estimated glomerular filtration rates (eGFR) &lt, 60 mL/min/1.73 m2, hemoglobin levels &lt, 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 &gt, 25 mL/kg/h in CVVH with AN69 membranes may reduce the mortality risk in these high-risk patients.

Acute kidney injury (AKI)-related fibrosis is emerging as a major driver of chronic kidney disease (CKD) development. Aberrant kidney recovery after AKI is multifactorial and still poorly understood. The accumulation of indoxyl sulfate (IS), a protein-bound uremic toxin, has been identified as a detrimental factor of renal fibrosis. However, the mechanisms underlying IS-related aberrant kidney recovery after AKI is still unknown. The present study aims to elucidate the effects of IS on tubular damage and its involvement in the pathogenesis of AKI-to-CKD transition. Our results showed that serum IS started to accumulate associated with the downregulation of tubular organic anion transporter but not observed in the small-molecule uremic toxins of the unilateral ischemia–reperfusion injury (UIRI) without a contralateral nephrectomy model. Serum IS is positively correlated with renal fibrosis and binding immunoglobulin protein (BiP) and CAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) expression induction in the UIRI with a contralateral nephrectomy model (UIRI+Nx). To evaluate the effects of IS in the AKI-to-CKD transition, we administered indole, a precursor of IS, at the early stage of UIRI. Our results demonstrated IS potentiates renal fibrosis, senescence-associated secretory phenotype (SASP), and activation of endoplasmic reticulum (ER) stress, which is attenuated by synergistic AST-120 administration. Furthermore, we clearly demonstrated that IS exposure potentiated hypoxia–reperfusion (H/R) induced G2/M cell cycle arrest, epithelial–mesenchymal transition (EMT) and aggravated ER stress induction in vitro. Finally, the ER chemical chaperon, 4-phenylbutyric acid (4-PBA), successfully reversed the above-mentioned AKI-to-CKD transition. Taken together, early IS elimination in the early stage of AKI is likely to be a useful strategy in the prevention and/or treatment of the AKI-to-CKD transition.

Venous stenosis is the most common cause of arteriovenous fistula (AVF) failure in hemodialysis patients. For patients with AVF stenosis, the pressure over the antecedent part of the AVF stenotic lesion will increase if arterial inflow is sufficient. We report a chronic hemodialysis patient who received an angiographic examination for the juxta-anastomosis stenosis of his AVF. A unique feature of a collateral venous branch antecedent to the stenotic lesion was noted, resembling a musical sign as the “eighth note.” After percutaneous transluminal angioplasty, the eighth note attenuated markedly at once. Of note, the eighth note sign is not seen frequently, and thus we postulate that the formation of an eighth note sign on the radiocephalic fistula should fulfill the following requirements, including a sufficient arterial inflow, an adjacent collateral branch close enough to the arteriovenous anastomosis, a severe juxta-anastomotic stenotic lesion, and an intact ulnar venous drainage system.

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.

Serum bilirubin levels, which are determined by a complex interplay of various enzymes, including heme oxygenase-1 (HO-1) and uridine diphosphate–glucuronosyl transferase (UGT1A1), may be protective against progression of cardiovascular disease (CVD) in hemodialysis patients. However, the combined effect of HO-1 and UGT1A1*28 gene polymorphisms on CVD outcomes among hemodialysis patients is still unknown. This retrospective study enrolled 1080 prevalent hemodialysis patients and the combined genetic polymorphisms of HO-1 and UGT1A1 on serum bilirubin were analyzed. Endpoints were CVD events and all-cause mortality. Mean serum bilirubin was highest in patients with S/S + S/L of the HO-1 promoter and UGT1A1 7/7 genotypes (Group 1), intermediate in those with S/S + S/L of the HO-1 promoter and UGT1A1 7/6 + 6/6 genotypes (Group 2), and lowest in the carriers with the L/L HO-1 promoter and UGT1A1 7/6 + 6/6 genotypes (Group 3) (p < 0.001). During a median follow-up of 50 months, 433 patients developed CVD. Compared with patients in Group 3, individuals among Groups 1 and 2 had significantly lower risks for CVD events (adjusted hazard ratios (aHRs) of 0.35 for Group 1 and 0.63 for Group 2), respectively. Compared with the lower bilirubin tertile, the aHRs were 0.72 for the middle tertile and 0.40 for the upper tertile for CVD events. We summarized that serum bilirubin as well as HO-1 and UGT1A1 gene polymorphisms were associated with CVD among patients receiving chronic hemodialysis.

Matrix metalloproteinase 9 (MMP-9) expression is upregulated in vascular inflammation and participates in vascular remodeling, including aneurysm dilatation and arterial neointima development. Neointima at the arteriovenous (AV) fistula anastomosis site primarily causes AV fistula stenosis and failure, however, the effects of MMP-9 on perioperative AV fistula remodeling remain unknown. Therefore, we created AV fistulas (end-to-side anastomosis) in wild-type (WT) and MMP-9 knockout mice with chronic kidney disease to further clarify this. Neointima progressively developed in the AV fistula venous segment of WT mice during the four-week postoperative course, and MMP-9 knockout increased the lumen area and attenuated neointima size by reducing smooth muscle cell and collagen components. Early perioperative AV fistula mRNA sequencing data revealed that inflammation-related gene sets were negatively enriched in AV fistula of MMP-9 knockout mice compared to that in WT mice. qPCR results also showed that inflammatory genes, including tumor necrosis factor-a (TNF-α), monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1), were downregulated. In addition, Western blot results showed that MMP-9 knockout reduced CD44 and RAC-alpha serine/threonine-protein kinase (Akt) and extracellular signal-regulated kinases (ERK) phosphorylation. In vitro, MMP-9 addition enhanced IL-6 and MCP-1 expression in vascular smooth muscle cells, as well as cell migration, which was reversed by an MMP-9 inhibitor. In conclusion, MMP-9 knockout attenuated AV fistula stenosis by reducing perioperative vascular inflammation.

Decoy receptor 3 (DcR3), also known as tumor necrosis factor receptor superfamily member 6b (TNFRSF6B), was recently identified as a novel biomarker for predicting progression of kidney diseases with potential immune modulation. The purpose of this review is to discuss the current evidence related to DcR3 in kidney diseases and to compare the differences between human and animal studies both in vivo and in vitro. High serum DcR3 predicts the occurrence of peritonitis in patients receiving chronic peritoneal dialysis and is positively correlated with inflammatory markers such as interleukin-6, high-sensitivity C-reactive protein, and adhesion molecules in patients on maintenance hemodialysis (HD). Higher serum DcR3 levels not only independently predict cardiovascular and all-cause mortality in HD patients but also identify older adults on HD at risk of protein-energy wasting in combination with a low geriatric nutritional risk index. Recently, renal tubular epithelial cells (RTECs) expressing DcR3 have also been used to predict progression of chronic kidney disease. Expression of DcR3 was correlated with a 2-fold increase in serum creatinine or failure of kidney allograft. DcR3 could protect renal myofibroblasts against Fas-induced apoptosis and subsequently lead to renal fibrosis. Locally expressed DcR3 in the RTECs may suppress the FasL-Fas-mediated apoptosis of T cells, resulting in an accumulation of allo-reactive T cells. In addition to traditional biological functions, recombinant DcR3.Fc and cytomegalovirus promoter-driven human DcR3 plasmid are able to modulate the activation and differentiation of dendritic cells and macrophages via "non-decoy" action. Both progressive IgA nephropathy and autoimmune crescentic glomerulonephritis in mice can be suppressed after hydrodynamics-based gene delivery of DcR3 plasmid. DcR3-mediated effects in vitro could be surveyed via over-expressing DcR3 or addition of recombinant DcR3.Fc, and CD68-driven DcR3 transgenic mice are suitable for investigating systemic effect in vivo. Inhibition of DcR3 expression in human may be a promising approach for pathomechanism.

Background: The two ends of arteriovenous graft (AVG) are anastomosed to the upper limb vessels by surgery for hemodialysis therapy. However, the size of upper limb vessels varies to a large extent among different individuals. Methods: According to the shape and size of neck vessels quantified from the preoperative computed tomography angiographic scan, the ethylene-vinyl acetate (EVA)-based AVG was produced in H-shape by the three-dimensional (3D) printer and then sterilized. This study investigated the function of this novel 3D-printed AVG in vitro and in vivo. Results: This 3D-printed AVG can be implanted in the rabbit’s common carotid artery and common jugular vein with ease and functions in vivo. The surgical procedure was quick, and no suture was required. The blood loss was minimal, and no hematoma was noted at least 1 week after the surgery. The blood flow velocity within the implanted AVG was 14.9 ± 3.7 cm/s. Additionally, the in vitro characterization experiments demonstrated that this EVA-based biomaterial is biocompatible and possesses a superior recovery property than ePTFE after hemodialysis needle cannulation. Conclusions: Through the 3D printing technology, the EVA-based AVG can be tailor-made to fit the specific vessel size. This kind of 3D-printed AVG is functioning in vivo, and our results realize personalized vascular implants. Further large-animal studies are warranted to examine the long-term patency.

Emerging evidence suggests that intestinal dysbiosis plays an important role in host inflammation locally and systemically. Such pathological condition is even more prevailing in patients with chronic kidney disease (CKD). Of note, indoxyl sulphate (IS), a gut-derived uremic toxin, is notorious for its pro-inflammatory feature in CKD patients. IS accumulates in the body as the urinary excretion of uremic toxins is impaired, and further worsens the kidney function in a vicious cycle to CKD. Dietary restriction in vegetables, fruits and yogurt leads to the predominance of indole-producing intestinal microbial flora and further exaggerates the accumulation of IS in CKD patients. Recently, interventional studies have shown that circulating IS can be reduced by dietary prebiotic and/or probiotic supplements. However, further randomized controlled trials are warranted to examine whether such beneficial effect of dietary prebiotic/probiotic supplements could be extrapolated to better hard outcomes in CKD population. In this review, we would also like to emphasize the importance of achieving sufficient intake of dietary fibre by proper vegetable pre-treatment and accurate fruit selection, instead of directly avoiding these potassium-rich yet fibre-rich and base-producing foods.

Background Acute kidney injury (AKI) is an emerging global healthcare issue without effective therapy yet. Autophagy recycles damaged organelles and helps maintain tissue homeostasis in acute renal ischemia-reperfusion (I/R) injury. Hypoxic mesenchymal stem cells (HMSCs) represent an innovative cell-based therapy in AKI. Moreover, the conditioned medium of HMSCs (HMSC-CM) rich in beneficial trophic factors may serve as a cell-free alternative therapy. Nonetheless, whether HMSCs or HMSC-CM mitigate renal I/R injury via modulating tubular autophagy remains unclear. Methods Renal I/R injury was induced by clamping of the left renal artery with right nephrectomy in male Sprague-Dawley rats. The rats were injected with either PBS, HMSCs, or HMSC-CM immediately after the surgery and sacrificed 48 h later. Renal tubular NRK-52E cells subjected to hypoxia-reoxygenation (H/R) injury were co-cultured with HMSCs or treated with HMSC-CM to assess the regulatory effects of HSMCs on tubular autophagy and apoptosis. The association of tubular autophagy gene expression and renal recovery was also investigated in patients with ischemic AKI. Result HMSCs had a superior anti-oxidative effect in I/R-injured rat kidneys as compared to normoxia-cultured mesenchymal stem cells. HMSCs further attenuated renal macrophage infiltration and inflammation, reduced tubular apoptosis, enhanced tubular proliferation, and improved kidney function decline in rats with renal I/R injury. Moreover, HMSCs suppressed superoxide formation, reduced DNA damage and lipid peroxidation, and increased anti-oxidants expression in renal tubular epithelial cells during I/R injury. Co-culture of HMSCs with H/R-injured NRK-52E cells also lessened tubular cell death. Mechanistically, HMSCs downregulated the expression of pro-inflammatory interleukin-1β, proapoptotic Bax, and caspase 3. Notably, HMSCs also upregulated the expression of autophagy-related LC3B, Atg5 and Beclin 1 in renal tubular cells both in vivo and in vitro. Addition of 3-methyladenine suppressed the activity of autophagy and abrogated the renoprotective effects of HMSCs. The renoprotective effect of tubular autophagy was further validated in patients with ischemic AKI. AKI patients with higher renal LC3B expression were associated with better renal recovery. Conclusion The present study describes that the enhancing effect of MSCs, and especially of HMCSs, on tissue autophagy can be applied to suppress renal tubular apoptosis and attenuate renal impairment during renal I/R injury in the rat. Our findings provide further mechanistic support to HMSCs therapy and its investigation in clinical trials of ischemic AKI.

Background Frailty, a syndrome characterized by a decline in function reserve, is common in older patients with heart failure (HF) and is associated with prognosis. This study aimed to evaluate the impact of frailty on outcomes in older patients with preserved and reduced cardiac function. Methods In total, 811 adults aged ≥65 years were consecutively enrolled from 2009 to 2018. HF was diagnosed according to the ICD9 code and a 2D echocardiogram was categorized by reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). The index date was registered at the time of HF. All patients received a comprehensive geriatric assessment, and clinical outcomes were examined with adjustment of the other prognostic variables. Results Mean age was 80.5 ± 7.1 years. The prevalence of HF, HFpEF, HFrEF, Fried, and Rockwood frailty indicators was 28.5, 10.4, 9.7, 52.5, and 74.9%, respectively. At baseline, scores in the Timed Up and Go test was closely associated with the severity of HF, either with HFpEF or HFrEF. After a mean follow-up of 3.2 ± 2.0 years, we found that HF patients with low handgrip strength (HGS) had the poorest survival, followed by non-HF patients with decreased HGS, and HF with fair HGS in comparison with non-HF with fair HGS (p = 0.008) if participants were arbitrarily divided into two HGS groups. In all patients, a high Rockwood frailty index was independently associated with increased mortality (adjusted hazard ratio [aHR] = 1.05; 95% confidence interval [CI]: 1.0004 to 1.10). In addition, the adjusted mortality HR was 3.42 with decreased HGS (95% CI: 1.03 to 11.40), 7.65 with use of mineralocorticoid receptor antagonist (95% CI: 2.22 to 26.32), and 1.26 with associated multi-comorbidities assessed by Charlson comorbidity index (95% CI: 1.05 to 1.51). Conclusions Our study results indicate that frailty and decreased physical functions were associated with HF. Besides, frailty and HGS predicted prognosis in the patients, and there was a combined effect of HF and low HGS on survival.

TRPA1, a nonselective cation channel, is expressed in sensory afferent that innervates peripheral targets. Neuronal TRPA1 can promote tissue repair, remove harmful stimuli and induce protective responses via the release of neuropeptides after the activation of the channel by chemical, exogenous, or endogenous irritants in the injured tissue. However, chronic inflammation after repeated noxious stimuli may result in the development of several diseases. In addition to sensory neurons, TRPA1, activated by inflammatory agents from some non-neuronal cells in the injured area or disease, might promote or protect disease progression. Therefore, TRPA1 works as a molecular sentinel of tissue damage or as an inflammation gatekeeper. Most kidney damage cases are associated with inflammation. In this review, we summarised the role of TRPA1 in neurogenic or non-neurogenic inflammation and in kidney disease, especially the non-neuronal TRPA1. In in vivo animal studies, TRPA1 prevented sepsis-induced or Ang-II-induced and ischemia-reperfusion renal injury by maintaining mitochondrial haemostasis or via the downregulation of macrophage-mediated inflammation, respectively. Renal tubular epithelial TRPA1 acts as an oxidative stress sensor to mediate hypoxia–reoxygenation injury in vitro and ischaemia–reperfusion-induced kidney injury in vivo through MAPKs/NF-kB signalling. Acute kidney injury (AKI) patients with high renal tubular TRPA1 expression had low complete renal function recovery. In renal disease, TPRA1 plays different roles in different cell types accordingly. These findings depict the important role of TRPA1 and warrant further investigation.

Additional file 1: Supplementary Table 1. Dosage of immunosuppressive agents in adult-onset minimal change disease.

Additional file 1 Supplementary information accompanies this paper at BMC Geriatrics online.

This case report describes a 56-year-old woman receiving regular hemodialysis for three years who presented with an unsteady gait for one month, dysarthria, and frequent choking on liquids for two weeks. Brain MRI revealed a characteristic "lentiform fork sign" with hyperintense T2W/FLAIR signal in the bilateral lentiform nuclei and restricted diffusion in bilateral globus pallidus. She was inadvertently prescribed metformin 1,000 mg per day one month ago by a physician who was unaware of her end-stage kidney disease. After intensive hemodialysis therapy with eight hemodialysis sessions within 12 days, her neurological deficits fully resolved. Clinicians should be aware of metformin-induced encephalopathy, presenting with relevant medication history, neurological symptoms, and the lentiform fork sign.

Background: Di(2-ethylhexyl)phthalate (DEHP) is one of the phthalates most widely used to manufacture various plastic products. However, the potential effects of DEHP on erythropoiesis have not been investigated comprehensively. Here, we aimed to investigate whether DEHP modulate the function of haematopoietic stem and progenitor cells (HSPCs) to influence erythropoiesis, and to explore the associated mechanisms.Results: In the present study, human cell lines with a capacity to differentiate into erythroid cells and murine bone marrow cells were treated with DEHP. DEHP not only impaired HSPC function but also suppressed erythroid differentiation in a dose-dependent manner. In addition, DEHP removal restored HSPC activity. To explore how DEHP interferes with erythroid differentiation, we focused on energy metabolism and Klotho expression. DEHP suppressed erythroid differentiation via upregulation of Klotho expression in erythroblasts and not via cellular bioenergetic modulation.Conclusions: Here, we have demonstrated a novel pathophysiological role of DEHP in erythroid differentiation. DEHP impaired erythroid differentiation by inducing Klotho expression and not by reprogramming cellular bioenergetic profiles during differentiation.

Background: Immunoglobulin M (IgM) mesangial deposition in pediatric minimal change disease (MCD) has been reported to be associated with steroid dependence and poor renal outcomes. However, the evidence regarding the impact of IgM mesangial deposition on the treatment responses or outcomes in adult-onset MCD is lacking.Methods: In this retrospective cohort study, 37 adult patients with MCD received kidney biopsy from January 2010 to May 2020. According to IgM mesangial deposition by immunofluorescence microscopy, the patients were divided into two groups (12 patients with positive IgM deposition; 25 patients with negative IgM deposition). We analyzed the clinical features, the dosage of immunosuppressive agents, and the response to treatment for two years between the two groups.Results: Regarding the clinical symptoms, the dosage of immunosuppressive treatment, and the time to remission, there was no statistically significant difference between the two groups. Compared to the negative IgM group, the frequency of relapses was significantly higher in the positive IgM group within the two-year follow-up period (the negative IgM group 0.25 episodes/year; the positive IgM group 0.75 episodes/year, p = 0.029). Furthermore, multivariate linear regression revealed that the positivity of IgM mesangial deposition is independently associated with the frequency of relapses (regression coefficient B 0.450, 95% CI 0.116-0.784, p = 0.010).Conclusions: Our findings indicated that adult-onset MCD patients with IgM mesangial deposition have a high risk of relapses. Therefore, prolonged and combined immunosuppressive therapy with close follow-up may be considered in MCD adults with IgM mesangial deposition.

Background We explored the long-term safety and efficacy of ferric citrate in hemodialysis patients in Taiwan, and further evaluated the iron repletion effect and change of iron parameters by different baseline groups. Methods This was a 12-month, Phase IV, multicenter, open-label study. The initial dose of ferric citrate was administered by patients’ clinical condition and further adjusted to maintain serum phosphorus at 3.5–5.5 mg/dL. The primary endpoint was to assess the safety profiles of ferric citrate. The secondary endpoints were to evaluate the efficacy by the time-course changes and the number of subjects who achieved the target range of serum phosphorus. Results A total of 202 patients were enrolled. No apparent or unexpected safety concerns were observed. The most common treatment-emergent adverse events were gastrointestinal-related with discolored feces (41.6%). Serum phosphorus was well controlled, with a mean dose of 3.35±1.49 g/day, ranging from 1.5 to 6.0 g/day. Iron parameters were significantly improved. The change from baseline of ferritin and TSAT were 227.17 ng/mL and 7.53%, respectively (p-trend Conclusions Ferric citrate is an effective phosphate binder with favorable safety profile in ESRD patients. The iron-repletion by ferric citrate is effective, and the increase is limited in patients with a higher baseline. In addition to controlling hyperphosphatemia, ferric citrate also shows additional benefits in the treatment of renal anemia. Clinical trial registration ClinicalTrials.gov ID: NCT03256838; 12/04/2017.

Sepsis survivors have a higher risk of long-term complications. Acute kidney injury (AKI) may still be common among sepsis survivors after discharge from sepsis. Therefore, our study utilized an artificial-intelligence-based machine learning approach to predict future risks of rehospitalization with AKI between 1 January 2008 and 31 December 2018. We included a total of 23,761 patients aged ≥ 20 years who were admitted due to sepsis and survived to discharge. We adopted a machine learning method by using models based on logistic regression, random forest, extra tree classifier, gradient boosting decision tree (GBDT), extreme gradient boosting, and light gradient boosting machine (LGBM). The LGBM model exhibited the highest area under the receiver operating characteristic curves (AUCs) of 0.816 to predict rehospitalization with AKI in sepsis survivors and followed by the GBDT model with AUCs of 0.813. The top five most important features in the LGBM model were C-reactive protein, white blood cell counts, use of inotropes, blood urea nitrogen and use of diuretics. We established machine learning models for the prediction of the risk of rehospitalization with AKI in sepsis survivors, and the machine learning model may set the stage for the broader use of clinical features in healthcare.

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 Conclusion Physical activity of 7.5 to

Background Diabetes has a pronounced effect on the peripheral vasculature. The accumulation of advanced glycation end products (AGEs) is regarded as the crucial mechanism responsible for vascular damage in diabetes, but it is not easy to be avoided from food. In this study, we aimed to investigate the effects of an oral absorbent, AST-120, on the accumulation of AGEs and changes in blood flow recovery in diabetic mice. Methods The mice were divided into four groups, wild-type (WT) mice without treatment, WT mice treated with 5% AST-120 mixed into with pulverized chow, streptozotocin-induced diabetes mellitus (DM) mice, and DM mice treated with 5% AST-120. Six weeks after hind-limb ischemia surgery, blood flow reperfusion, histology, plasma AGE, and cytokine were examined. Bone marrow cells were cultured and derived into macrophages to evaluate the effects of AGEs on macrophage polarization. Results Plasma AGEs were significantly increased in diabetic mice. AST-120 could bind to AGEs and reduced their plasma concentrations. Histological analysis revealed fewer collateral vessels with corresponding impairment of blood flow recovery in diabetic mice. In these mice, AGE-positive and AGE receptor-positive macrophages were numerous in ischemic limbs when compared with non- diabetic mice. In diabetic mice, macrophages in ischemic tissues demonstrated greater M1 polarization than M2 polarization; this pattern was reversed in the AST-120 treatment group. The change in macrophage polarization was associated with corresponding expression of pro-inflammatory and pro-angiogenic cytokines in the ischemic tissues. In cell cultures, AGEs triggered the transformation of bone marrow-derived macrophages into M1 phenotype. The alterations in the polarization of macrophages were reversed after treatment with AST-120. Conclusions Oral administration of AST-120 decreased the serum levels of AGEs in diabetic mice and improved neovascularization of ischemic limbs. This benefit may be due to, at least partially, the alterations in macrophage polarization and the associated changes in inflammatory and angiogenic cytokines.