Publications by authors named "XiaoQiang Ding"

198 Publications

Prostaglandin E induced cardiac hypertrophy through EP2 receptor-dependent activation of β-catenin in 5/6 nephrectomy rats.

ESC Heart Fail 2021 Apr 6. Epub 2021 Apr 6.

Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China.

Aims: Prostaglandin E (PGE2) is involved in the development of cardiac hypertrophy. However, whether PGE2 regulates the chronic kidney disease-associated cardiac hypertrophy and the tentative mechanism remains to be elucidated.

Methods And Results: We explored the effect of PGE2 receptor inhibitors on cardiac hypertrophy in vitro and in a 5/6 nephrectomy (5/6NT) rat model using quantitative reverse transcription polymerase chain reaction, western blotting, enzyme-linked immunosorbent assay, immunohistochemical staining, and immunofluorescence staining assays. The result showed that EP2 and EP4 receptors were both up-regulated in the PGE2-treated cardiomyocyte cells. PGE2 treatment enhanced active β-catenin (non-phosphorylated) signalling through mediating EP2 and EP4 receptors. Interestingly, inhibition of EP2 receptor suppressed PGE2-induced cardiomyocyte hypertrophy and cardiac fibrosis-related proteins in vitro. In the 5/6NT rat model, the increased secretion PGE2 was identified in the 5/6NT rat model for 2 weeks (P = 0.0251). EP2 receptor inhibitor administration significantly improved the cardiac function and fibrosis in 5/6NT rats.

Conclusions: Our study demonstrated that inhibition of EP2 receptor could improve PGE2-induced cardiac hypertrophy in 5/6NT rats. The exploration of these mechanisms may contribute to the optimization of therapy in chronic kidney disease accompanied cardiac hypertrophy in clinic.
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http://dx.doi.org/10.1002/ehf2.13269DOI Listing
April 2021

Decreased Peripheral Naïve T Cell Number and Its Role in Predicting Cardiovascular and Infection Events in Hemodialysis Patients.

Front Immunol 2021 17;12:644627. Epub 2021 Mar 17.

Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China.

Patients with end-stage renal disease (ESRD) are at high risk of morbidity and mortality from cardiovascular and infectious diseases, which have been found to be associated with a disturbed immune response. Accelerated T-cell senescence is prevalent in these patients and considered a significant factor contributing to increased risk of various morbidities. Nevertheless, few studies have explicated the relevance of T-cell senescence to these fatal morbidities in ESRD patients. In this study, we designed a longitudinal prospective study to evaluate the influence of T-cell senescence on cardiovascular events (CVEs) and infections in hemodialysis (HD) patients. Clinical outcomes of 404 patients who had been on HD treatment for at least 6 months were evaluated with respect to T-cell senescence determined using flow cytometry. We found that T-cell senescence was associated with systemic inflammation. High-sensitivity C-reactive protein was positively associated with decreased naïve T cell levels. Elevated tumor necrosis factor-α and interleukin 6 levels were significantly associated with lower central memory T cell and higher T effector memory CD45RA cell levels. Decreased CD4 naïve T cell count was independently associated with CVEs, whereas decreased CD8 naïve T cell count was independently associated with infection episodes in HD patients. In conclusion, HD patients exhibited accelerated T-cell senescence, which was positively related to inflammation. A reduction of naïve T cell could be a strong predictor of CVEs and infection episodes in HD patients.
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http://dx.doi.org/10.3389/fimmu.2021.644627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009982PMC
March 2021

Transfer RNA Fragments in the Kidney in Hypertension.

Hypertension 2021 May 29;77(5):1627-1637. Epub 2021 Mar 29.

Center of Systems Molecular Medicine, Department of Physiology, Medical College of Wisconsin, Milwaukee (X.P., X.G., Y.L., M.K.M., P.L., M.L.).

[Figure: see text].
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.121.16994DOI Listing
May 2021

Vancomycin Associated Acute Kidney Injury: A Longitudinal Study in China.

Front Pharmacol 2021 8;12:632107. Epub 2021 Mar 8.

Department of Pharmacy, Zhongshan Hospital Fudan University, Shanghai, China.

Vancomycin-associated acute kidney injury (VA-AKI) is a recognizable condition with known risk factors. However, the use of vancomycin in clinical practices in China is distinct from other countries. We conducted this longitudinal study to show the characteristics of VA-AKI and how to manage it in clinical practice. We included patients admitted to hospital, who received vancomycin therapy between January 1, 2016 and June 2019. VA-AKI was defined as a patient having developed AKI during vancomycin therapy or within 48 h following the withdrawal of vancomycin therapy. A total of 3719 patients from 7058 possible participants were included in the study. 998 patients were excluded because of lacking of serum creatinine measurement. The incidence of VA-AKI was 14.3%. Only 32.3% (963/2990) of recommended patients performed therapeutic drug monitoring of vancomycin. Patients with VA-AKI were more likely to concomitant administration of cephalosporin (OR 1.55, 95% CI 1.08-2.21, = 0.017), carbapenems (OR 1.46, 95% CI 1.11-1.91, = 0.006) and piperacillin-tazobactam (OR 3.12, 95% CI 1.50-6.49, = 0.002). Full renal recovery (OR 0.208, = 0.005) was independent protective factors for mortality. Compared with acute kidney injury stage 1, AKI stage 2 (OR 2.174, = 0.005) and AKI stage 3 (OR 2.210, = 0.005) were independent risk factors for fail to full renal recovery. Lack of a serum creatinine measurement for the diagnosis of AKI and lack of standardization of vancomycin therapeutic drug monitoring should be improved. Patient concomitant with piperacillin-tazobactam are at higher risk. Full renal recovery was associated with a significantly reduced morality.
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http://dx.doi.org/10.3389/fphar.2021.632107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982802PMC
March 2021

Relationship Between Gene Polymorphism of Methylenetetrahydrofolate Reductase C677T and Left Ventricular Hypertrophy in Chinese Patients with Chronic Kidney Disease.

Lab Med 2021 Mar 8. Epub 2021 Mar 8.

Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China.

Objective: This study aimed to investigate the relationship between the gene polymorphism of methylenetetrahydrofolate reductase (MTHFR) C677T and left ventricular hypertrophy (LVH) in patients with chronic kidney disease (CKD).

Methods: A total of 763 Chinese patients with CKD undergoing genetic testing were included in the study. The association between the gene polymorphism of MTHFR C677T and echocardiographic parameters was analyzed through univariate and multivariate analyses.

Results: We found a remarkably positive association between MTHFR C677T gene polymorphism and LVH indexes, including interventricular septal thickness (F = 3.8; P = .022), left ventricular posterior wall thickness (F = 3.0; P = .052), left ventricular mass (F = 3.9; P = .022), and left ventricular mass index (F = 2.6; P = .075). After adjusting for the potential confounders linking the polymorphism,we found that the positive association between the polymorphism and LVH indexes still existed in patients with CKD in some multiple linear regression models (P <.05).

Conclusion: MTHFR C677T gene polymorphism may be a genetic susceptibility marker for the development of LVH in patients with CKD.
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http://dx.doi.org/10.1093/labmed/lmab004DOI Listing
March 2021

Association of N-Terminal Pro-brain Natriuretic Peptide With Volume Status and Cardiac Function in Hemodialysis Patients.

Front Cardiovasc Med 2021 22;8:646402. Epub 2021 Feb 22.

Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China.

N-terminal-pro-brain natriuretic peptide (NT-pro BNP) is secreted by cardiomyocytes in cases of cardiac structure disorder and volume overload. However, the relationship between NT-pro BNP level and body fluid status in dialysis patients with reduced cardiac ejection function (EF) is uncertain. Therefore, we aimed to investigate this relationship. We enrolled patients who had been receiving hemodialysis for >3 months. Blood sample, transthoracic echocardiographic, and bioimpedance spectroscopy measurements were performed during a midweek non-dialysis day. The predictive value of NT-pro BNP in hemodialysis patients with volume overload was analyzed. A total of 129 hemodialysis patients (74 men and 55 women; mean age: 59.4 ± 13.0 years) were recruited. The average hemodialysis duration was 55.5 (23.9-93.4) months, the NT-pro BNP level was 4992 (2,033-15,807) pg/mL, and the value of overhydration was 2.68 ± 0.19 (-1.9 to 12.2) L. The NT-pro BNP level was independently correlated with overhydration in both the LVEF ≥ 60% (β = 0.236, = 0.044) and LVEF <60% (β = 0.516, = 0.032) groups, even after adjustments for potentially confounding variables. In receiver operating characteristic curves of NT-pro BNP for predicting volume overload, the area under the curve was 0.783 [95% CI (0.688-0.879), < 0.001) and 0.788 [95% CI (0.586-0.989), < 0.001] in the LVEF ≥ 60% and LVEF < 60% groups, respectively. NT-pro BNP is a predictive factor for volume overload in hemodialysis patients with or without EF declines.
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http://dx.doi.org/10.3389/fcvm.2021.646402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937607PMC
February 2021

Association between urbanisation and the risk of hyperuricaemia among Chinese adults: a cross-sectional study from the China Health and Nutrition Survey (CHNS).

BMJ Open 2021 Mar 10;11(3):e044905. Epub 2021 Mar 10.

Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China

Objective: To explore the association between urbanicity and hyperuricaemia (HUA) and whether urbanicity is an independent risk factor for HUA in Chinese adults.

Design: Data analysis from a cross-sectional survey.

Setting And Participants: 8579 subjects aged 18 years or older were enrolled in the study from the 2009 wave of the China Health and Nutrition Survey to analyse the association between urbanicity and HUA. We divided them into three categories according to urbanisation index (low, medium and highly urbanised groups).

Main Outcome Measures: HUA was defined as serum uric acid ≥7 mg/dL in men and ≥6 mg/dL in women.

Results: The prevalence of HUA in low, medium and highly urbanised groups was 12.2%, 14.6% and 19.8%, respectively. The independent factors influencing serum uric acid included age, gender, hypertension, diabetes, chronic kidney disease, drinking, obesity and community-level urbanisation index (β=0.016, p<0.001). The risk of HUA in the highly urbanised group was significantly higher than that of the low urbanised group (OR 1.771, 95% CI 1.545 to 2.029, p<0.001), even after adjusting for other covariates (OR 1.661, 95% CI 1.246 to 2.212, p=0.001). In a subgroup analysis, we found that age, gender, comorbidity (such as hypertension, diabetes, obesity and chronic kidney disease) and physical activity affected the association between urbanisation and the risk of HUA.

Conclusions: Our findings suggest that living in highly urbanised areas is linked with higher risk of HUA independent of cardiometabolic and health-related behavioural risk factors, which have been shown to increase along with urbanisation.
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http://dx.doi.org/10.1136/bmjopen-2020-044905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7949434PMC
March 2021

Pathological assessment of chronic kidney disease with DWI: Is there an added value for diffusion kurtosis imaging?

J Magn Reson Imaging 2021 Feb 26. Epub 2021 Feb 26.

Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Medical Imaging, Shanghai, 200032, China.

Background: Chronic kidney disease (CKD) is a worldwide health problem, precise functional and pathological assessment is beneficial to better treatment. Diffusion kurtosis imaging (DKI) can evaluate non-Gaussian diffusion and may help to assess renal pathology and function.

Purpose: To assess pathological and functional alterations in CKD using DKI compared with diffusion-weighted imaging (DWI).

Study Type: Prospective study.

Population: 70 CKD patients and 20 healthy volunteers.

Field Strength: 1.5 T.

Assessment: All participants underwent DKI, and apparent diffusion coefficient (ADC), mean diffusivity (MD), and mean kurtosis (MK) of renal parenchyma were acquired. Correlation between renal parenchymal ADC, MD, MK, and estimated glomerular filtration rate (eGFR), pathological scores were assessed. The diagnostic efficacy of ADC, MD, and MK for assessing the degree of renal pathological injury were compared.

Statistical Tests: ANOVA, Spearman correlation analysis, and ROC curve analysis.

Results: The cortical ADC, MD were significantly higher than medulla for all participants, whereas medullary MK was significantly higher than cortex (P < 0.01). Whether eGFR reduced or not, renal parenchymal MK were significantly higher in patients than controls (P < 0.05). Positive correlation was found between eGFR and ADC (cortex, r = 0.562; medulla, r = 0.527), and negative correlation between eGFR and MK (cortex, r = -0.786; medulla, r = -0.709) (all P < 0.001). There was positive correlation between MK and glomerular injury (cortex, r = 0.681; medulla, r = 0.652), tubulointerstitial lesion (cortex, r = 0.650; medulla, r = 0.599) (all P < 0.001). For discrimination between mild and m-s renal injury group, the AUC values of ADC, MD, MK were cortex: 0.723, 0.655, 0.864 and medulla: 0.718, 0.581, 0.829. The AUC values of ADC, MD, MK were cortex: 0.708, 0.679, 0.770 and medulla: 0.713, 0.830, 0.780 for differentiating control group from mild renal injury group.

Data Conclusion: DKI is practicable for noninvasive assessment of renal pathology and function of CKD, DKI offer better diagnostic performance than DWI. Evidence Level 1 Technical Efficacy 2.
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http://dx.doi.org/10.1002/jmri.27569DOI Listing
February 2021

Hemodilution is associated with underestimation of serum creatinine in cardiac surgery patients: a retrospective analysis.

BMC Cardiovasc Disord 2021 Jan 31;21(1):61. Epub 2021 Jan 31.

Department of Nephrology, Zhongshan Hospital, Shanghai Medical College, Fudan University, 180 Fenglin Road, Shanghai, 200032, China.

Background: Fluid overload is related to the development and prognosis of cardiac surgery-associated acute kidney injury (CSA-AKI). The study is to investigate the influence of serum creatinine (SCr) corrected by fluid balance on the prognosis of patients with cardiac surgery.

Methods: A retrospective study was conducted in 1334 patients who underwent elective cardiac surgery from January 1 to December 31, 2015. Kidney Disease: Improving Global Outcomes (KDIGO) criteria for AKI were applied to identify CSA-AKI. SCr was measured every 24 h during ICU period and was accordingly adjusted for cumulative fluid balance. Changes in SCr, defined as ∆Crea, were determined by difference between before and after adjustment for cumulative fluid balance. All patients were then divided into three groups: underestimation group (∆Crea ≥ P), normal group (P < ∆Crea < P) and overestimation group (∆Crea ≤ P).

Results: The incidence of AKI increased from 29.5% to 31.8% after adjustment for fluid balance. Patients in underestimation group showed prolonged length of ICU stay compared with normal group and overestimation group (3.2 [1.0-4.0] vs 2.1 [1.0-3.0] d, P < 0.001; 3.2  [1.0-4.0] vs 2.3 [1.0-3.0] d, P < 0.001). Length of hospital stay and mechanical ventilation dependent days in underestimation group were significantly longer than normal group (P < 0.001). Multivariate analysis showed age, baseline SCr and left ventricular ejection fraction were independently associated with underestimation of creatinine.

Conclusions: Cumulative fluid balance after cardiac surgery disturbs accurate measurement of serum creatinine. Patients with underestimation of SCr were associated with poor prognosis.
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http://dx.doi.org/10.1186/s12872-021-01879-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849106PMC
January 2021

Neutrophil to Lymphocyte Ratio as a Predictor of Long-Term Outcome in Peritoneal Dialysis Patients: A 5-Year Cohort Study.

Blood Purif 2021 Jan 28:1-7. Epub 2021 Jan 28.

Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China,

Introduction: The mortality of peritoneal dialysis (PD) patients remains high. The neutrophil to lymphocyte ratio (NLR), as an indicator of systemic inflammation, has been considered to be a predictor of cardiovascular and all-cause mortality in hemodialysis patients. The present study aims to investigate the relationship between NLR and long-term outcome in PD patients.

Materials And Methods: The study included patients who initiated PD for at least 3 months between January 1, 2013, and December 31, 2015. All the patients were followed up until death, cessation of PD, or to the end of the study (June 31, 2018). NLR was calculated as the ratio of neutrophils to lymphocytes.

Results: A total of 140 patients were included in this study. The median NLR reported was 2.87. Patients with lower NLR showed a higher survival rate than patients with higher NLR (log rank 6.886, p = 0.009). Furthermore, patients with higher NLR had a significantly higher cardiovascular mortality (log rank 5.221, p = 0.022). Multivariate Cox proportional hazards model showed that older age (HR 1.054, 95% CI 1.017-1.092, p = 0.004), higher Ca × P (HR 1.689, 95% CI 1.131-2.523, p = 0.010), and higher NLR (HR 2.603, 95% CI 1.037-6.535, p = 0.042) were independent predictors of increased all-cause mortality. NLR was also independently associated with cardiovascular mortality (HR 2.886, 95% CI 1.005-8.283, p = 0.039). Higher NLR (HR 2.667, 95% CI 1.333-5.337, p = 0.006), older age (HR 1.028, 95% CI 1.005-1.052, p = 0.016), and history of cardiovascular disease (HR 1.426, 95% CI 1.195-3.927, p = 0.031) were significantly independently associated with poor peritonitis-free survival in this study.

Conclusions: NLR could be a strong predictor of long-term outcome in PD patients.
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http://dx.doi.org/10.1159/000510552DOI Listing
January 2021

Paradoxical Association Between Intradialytic Blood Pressure Change and Long-Term Mortality with Different Levels of Interdialytic Weight Gain.

Int J Gen Med 2021 19;14:211-220. Epub 2021 Jan 19.

Division of Nephrology, Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.

Background: A greater interdialytic weight gain (IDWG) implies a greater ultrafiltration rate, which might lead to hemodynamic instability and intradialytic blood pressure (BP) change in hemodialysis patients. However, current studies have not explicated the impact of IDWG on the association between intradialytic BP changes and prognosis, especially in patients without cardiac dysfunction and diabetes. In this study, we aimed to explore the relationship between absolute intradialytic BP changes and mortality with different IDWG levels.

Methods: A total of 204 hemodialysis patients (without cardiac dysfunction and diabetes) were included in this prospective observation study, with a mean follow-up of 55.32±20.99 months. Initially, we collected IDWG, IDWG% (percentages according to dry weight), and pre-/post-BPs of 36 consecutive dialysis sessions during three months enrollment. And the average value of them was defined as baseline value. Patients were divided into 3 cohorts according to IDWG% tertiles (<3.3%, 3.3%-4.6%, ≥4.6%). Comparisons between different tertiles were analyzed.

Results: Compared to the low IDWG% group (tertile 1, T1), patients of high IDWG% group (tertile 3, T3) were younger, had higher ultrafiltration rate, less residual kidney function, lower BMI and dry weight, longer dialysis vintage and higher N terminal pro B type natriuretic peptide levels (<0.05). Correlations were found between IDWG% and intradialytic BP changes. Kaplan-Meier analysis and multivariate Cox regression model adjusted for demographic data, dialysis information and predialysis BPs indicated that greater absolute intradialytic BP changes were associated with worse prognosis in T1 group (<0.05). While in T3 group, less absolute intradialytic BP changes were associated with higher mortality (<0.05).

Conclusion: There is a paradoxical association between absolute intradialytic BP changes and long-term mortality with different IDWG levels. Both BP stability and volume balance are crucial to patients' prognosis.
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http://dx.doi.org/10.2147/IJGM.S288038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829598PMC
January 2021

Demographic, regional and temporal trends of hyperuricemia epidemics in mainland China from 2000 to 2019: a systematic review and meta-analysis.

Glob Health Action 2021 Jan;14(1):1874652

Department of Nephrology, Zhongshan Hospital, Fudan University , Shanghai, China.

Background: Hyperuricemia (HUA) is becoming a global public health problem and associated with multiple diseases.

Objective: We conducted a systematic review to synthesize the pooled prevalence of HUA in mainland China and delineate its demographic, regional, and temporal trends over the past two decades.

Methods: Systematic literature searches of PubMed, SCOPUS, Web of Science, the China National Knowledge Infrastructure (CNKI), and the Wanfang digital database were conducted to screen studies published from 1 January 2000 to 31 August 2019, reporting the prevalence of HUA in mainland China. The search strings were ('hyperuricemia' OR 'hyperuricaemia' OR 'uric acid') AND ('prevalence' OR 'epidemiology') AND 'China'. Article quality was appraised quantitatively from 11 items. Before formal meta-analysis, age-standardized prevalence was transformed. The random-effects model was applied to synthesize the pooled prevalence due to its high heterogeneity. Then we stratified the prevalence estimates by age, gender, area, nationality, and publication year for subgroup analysis.

Results: Totally 177 eligible studies with a whole population of 2,277,712 were included in the present meta-analysis. The pooled prevalence in mainland China was estimated at 16.4% (95% CI: 15.3%~17.6%). In studies with the onset age at 20 ~ 29 years old, males had a twice times higher HUA prevalence than females (21.5% vs. 8.9%). The prevalence of HUA was 13.7% (11.8%~15.7%) in people aged 15~ years old, 16.5% in 30~ (14.8%~18.4%), 17.9% in 40~ (16.4%~19.5%), 19.4% in 50~ (17.8%~21.0%), 20.5% in 60~ (18.8%~22.3%), and 24.9% in over 70 (22.9%~27.1%). Stratified by regions, southern (25.5%) and southwestern (21.2%) China shared the highest prevalence, and the lowest prevalence was observed in the northwest (12.6%). From 2001 to 2017, the prevalence estimates of HUA steadily climbed from 8.5% to 18.4% with minor fluctuations. Multiple regression revealed that HUA prevalence was positively correlated to the larger sample size, area, advanced onset age, and published year.

Conclusions: The last two decades witnessed the rapid growth prevalence of HUA in China. Early screening and personalized health education for HUA need to be given enough attention.
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http://dx.doi.org/10.1080/16549716.2021.1874652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833047PMC
January 2021

Pro-inflammatory cytokines as potential predictors for intradialytic hypotension.

Ren Fail 2021 Dec;43(1):198-205

Division of Nephrology, Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai, PR China.

Background: Intradialytic hypotension (IDH) is a common complication in maintaining hemodialysis (MHD) patients. Immune activation might be part of the mechanisms. However, the association between pro-inflammatory cytokines and blood pressure (BP) has not been deeply explored. So we aim to evaluate the potential role of pro-inflammatory cytokines in IDH.

Methods: MHD patients starting hemodialysis before January 2016 were enrolled in our retrospective study. Patients' characteristics, laboratory results, and intradialytic BP were collected. IDH was defined as nadir systolic BP ≤ 90 mmHg during hemodialysis. The definition of IDH group was that those who suffered from more than one hypotensive event during one month after the enrollment (10% of dialysis treatments). Spearman correlation analysis and logistic regression were employed to explore the relationship between pro-inflammatory cytokines and IDH.

Results: Among 390 patients, 72 were identified with IDH (18.5%). High levels of serum tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were observed in the IDH group ( < 0.001). Both TNF-α and IL-1β positively correlated with predialysis BP ( < 0.01). Receiver operating characteristic curve (ROC) analysis was used to evaluate the diagnostic accuracy of serum IL-1β and TNF-α for IDH. The area under the curve of IL-1β was 0.772 (95% CI: 0.708-0.836,  < 0.01), and that of TNF-α was 0.701 (95% CI: 0.620-0.781,  < 0.01). After adjusting for patients' characteristics, biochemical parameters, comorbid conditions, predialysis BP, and medications, elevated TNF-α and IL-1β were still risk factors for IDH.

Conclusion: Pro-inflammatory cytokines (TNF-α and IL-1β) could be potential predictors for IDH.
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http://dx.doi.org/10.1080/0886022X.2021.1871921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833080PMC
December 2021

Intradialytic systolic blood pressure variation can predict long-term mortality in patients on maintenance hemodialysis.

Int Urol Nephrol 2021 Apr 2;53(4):785-795. Epub 2021 Jan 2.

Division of Nephrology, Zhongshan Hospital, Shanghai Medical College, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China.

Purpose: It is unclear which time-points of intradialytic blood pressure (BP) best predict prognosis. Thus, it is important to assess the association between different time-points of intradialytic BP and prognosis in clinical practice.

Methods: We recruited patients who underwent hemodialysis from January 2014 to June 2014. Data about dialysis were collected, including intradialytic BP. Cox regression analysis was performed to examine the association between different time-points of intradialytic BP and clinical events, with a follow-up through December 31, 2019. The primary endpoint was all-cause mortality.

Results: A total of 216 patients were recruited and 62 (30.7%) patients died (6.1 per 100-person year) during the follow-up. Intradialytic SBP varied greatly in fatalities. Univariate and multivariate Cox regression models indicated that the adjusted hazard ratio for death was 1.80 and 5.06 when intradialytic systolic blood pressure (SBP) variation was analyzed in increments of 20 mmHg. Furthermore, we divided intradialytic SBP variation into three categories: < 15 mmHg, 15 ~ 30 mmHg,  ≥ 30 mmHg. Kaplan-Meier analysis indicated that both all-cause mortality and cardiovascular mortality increased significantly for patients with intradialytic SBP variation over 30 mmHg (P = 0.006 and 0.021). Univariate and multivariate Cox regression models indicated that the adjusted hazard ratio for death was 3.78 and 12.62 as intradialytic SBP variation ≥ 30 mmHg vs. intradialytic SBP variation < 15 mmHg.

Conclusion: Intradialytic SBP variation, rather than BP of specific intradialytic time-points, has the potential to predict long-term mortality in hemodialysis patients. BP stability is crucial for patients' prognosis.
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http://dx.doi.org/10.1007/s11255-020-02701-wDOI Listing
April 2021

Genistein Ameliorates Renal Fibrosis Through Regulation Snail via m6A RNA Demethylase ALKBH5.

Front Pharmacol 2020 19;11:579265. Epub 2020 Nov 19.

Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China.

Renal tubule-interstitial fibrosis is related to chronic kidney disease progression and a typical feature of the aging kidney. Epigenetic modifications of fibrosis-prone genes regulate the development of renal fibrosis. As a kind of "epigenetic diet", soy isoflavone genistein was reported to have renal protective action and epigenetic-modulating effects. However, its renal protection role and underlying mechanisms are yet to be fully clarified. Herein, we showed that genistein exhibits a demonstrable anti-fibrotic effect on kidney UUO (unilateral ureteral occlusion) model and renal epithelial cells model. The mechanism is strongly associated with epithelial-to-mesenchymal transition and m6A RNA demethylase ALKBH5. Mouse fibrotic kidneys induced by UUO exhibited adverse expression of renal fibrosis-related proteins and significant increases in the total m6A level. As an eraser, ALKBH5 showed severer suppression in the renal fibrosis process. However, genistein pretreatment restored ALKBH5 loss remarkably and reduced renal fibrosis, abnormal protein, and inflammatory markers. The examination of possible mechanisms revealed that genistein promoted ALKBH5 and maybe induced the level of mRNA m6A methylation in some epithelial-to-mesenchymal transition-related transcription factors. We found snail was the critical regulator and critical for the protective role of genistein. To verify the relationship between ALKBH5 and snail, we generated knockdown and overexpression of ALKBH5 cells . ALKBH5 knockdown enhanced the mesenchymal phenotype marker α-smooth muscle actin and snail expression. In agreement, overexpression ALKBH5 increased epithelial adhesion molecule E-cadherin and reduced snail expression. In conclusion, genistein increased renal ALKBH5 expression in UUO-induced renal fibrosis and reduced RNA m6A levels and ameliorates renal damages.
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http://dx.doi.org/10.3389/fphar.2020.579265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751752PMC
November 2020

Salvianolate ameliorates oxidative stress and podocyte injury through modulation of NOX4 activity in db/db mice.

J Cell Mol Med 2021 Jan 17;25(2):1012-1023. Epub 2020 Dec 17.

Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China.

Podocyte injury is associated with albuminuria and the progression of diabetic nephropathy (DN). NADPH oxidase 4 (NOX4) is the main source of reactive oxygen species (ROS) in the kidney and NOX4 is up-regulated in podocytes in response to high glucose. In the present study, the effects of Salvianolate on DN and its underlying mechanisms were investigated in diabetic db/db mice and human podocytes. We confirmed that the Salvianolate administration exhibited similar beneficial effects as the NOX1/NOX4 inhibitor GKT137831 treated diabetic mice, as reflected by attenuated albuminuria, reduced podocyte loss and mesangial matrix accumulation. We further observed that Salvianolate attenuated the increase of Nox4 protein, NOX4-based NADPH oxidase activity and restored podocyte loss in the diabetic kidney. In human podocytes, NOX4 was predominantly localized to mitochondria and Sal B treatment blocked HG-induced mitochondrial NOX4 derived superoxide generation and thereby ameliorating podocyte apoptosis, which can be abrogated by AMPK knockdown. Therefore, our results suggest that Sal B possesses the reno-protective capabilities in part through AMPK-mediated control of NOX4 expression. Taken together, our results identify that Salvianolate could prevent glucose-induced oxidative podocyte injury through modulation of NOX4 activity in DN and have a novel therapeutic potential for DN.
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http://dx.doi.org/10.1111/jcmm.16165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812253PMC
January 2021

High ultrafiltration rate induced intradialytic hypotension is a predictor for cardiac remodeling: a 5-year cohort study.

Ren Fail 2021 Dec;43(1):40-48

Division of Nephrology, Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai, P. R. China.

Background: Intradialytic-hypotension (IDH) is a common complication of hemodialysis. High ultrafiltration rate (UFR) might lead to IDH. However, the relationships between UFR, IDH, and cardiac remodeling among hemodialysis patients in the long-term have not been deeply explored.

Methods: This retrospective cohort study collected clinical and echocardiographic data. Patients were enrolled from 1 January 2014 to 31 March 2014 and were followed-up for 5-year. Those who suffered from more than four hypotensive events during three months (10% of dialysis treatments) were defined as the IDH group. Subgroup analysis was done according to the UFR of 10 ml/h/kg. Associations between UFR, IDH, and alterations of cardiac structure/function were analyzed.

Results: Among 209 patients, 96 were identified with IDH (45.9%). The survival rate of IDH patients was lower than that of no-IDH patients (65.5% vs. 81.4%,  = .005). In IDH group, decreased ejection fraction (EF), larger left atrium diameter index (LADI), and left ventricular mass index (LVMI) ( < .05) were observed at the end of the follow-up. In multivariate logistic model, the interaction between UFR and IDH was notably associated with LVMI variation ( = 1.37). After adjusting covariates, UFR was still an independent risk factor of LVMI variation ( = 1.52) in IDH group. In subsequent analysis, we divided patients according to UFR 10 ml/h/kg. For IDH-prone patients, decreased EF, larger LADI, and LVMI ( < .05) were observed at the end of the study only in high-UFR group.

Conclusions: UFR and IDH have interactions on cardiac remodeling. High ultrafiltration rate induced IDH is a predictor for cardiac remodeling in long-term follow-up.
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http://dx.doi.org/10.1080/0886022X.2020.1853570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745843PMC
December 2021

Correction to: The Association Between Renal Tubular Dysfunction and Zinc Level in a Chinese Population Environmentally Exposed to Cadmium.

Biol Trace Elem Res 2020 Nov 26. Epub 2020 Nov 26.

Department of Occupational Medicine, School of Public Health, Fudan University, 150 Dongan road, Shanghai, 200032, China.

The original version of this article unfortunately contained a mistake.
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http://dx.doi.org/10.1007/s12011-020-02403-5DOI Listing
November 2020

Indoxyl sulfate and high-density lipoprotein cholesterol in early stages of chronic kidney disease.

Ren Fail 2020 Nov;42(1):1157-1163

Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China.

Background: High IS level has been demonstrated to be associated with vascular calcification and lymphocyte functional disorders, which are both risk factors of CVD. Low HDL-c level is a risk factor of CVD in CKD patients. This study was designed to explore the potential relationship between IS and HDL-c levels in early stages of CKD population.

Methods: Patients of CKD stage 1-3 were enrolled in this cross-sectional study. Correlations between HDL-c and IS levels were investigated among various clinicopathological variables through independent samples test and multivariate logistic regression.

Results: A total of 205 CKD patients (96 men) aged 43.27 ± 13.80 years old were included in this research. There were 96 patients (46 men) in CKD stage1 and 109 (50 men) in CKD stage 2 or stage 3. IS levels were significantly higher in CKD 2 + 3 group (1.50 ± 1.74 μg/ml 0.94 ± 0.66 μg/ml,  = 0.007), while HDL-c levels were lower (1.19 ± 0.39 mmol/L 1.33 ± 0.45 mmol/L,  = 0.017) compared to CKD 1 group. Among all the patients, a negative correlation was observed between IS and HDL-c levels (r = -0.244,  = 0.001). IS level was an independent risk factor for low HDL-c (<1.04 mmol/L) incidence even after controlling for potential confounders including concomitant disease, age, sex, blood pressure, BMI and laboratory biochemical test including eGFR (OR = 1.63, 95% CI: 1.11-2.39,  = 0.013). IS and HDL-c were both risk factors for predicting CKD stage 3.

Conclusions: In early CKD stages, low HDL-c level is associated with increased IS levels, which may be an important contributor in the development of dyslipidemia in CKD patients.
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http://dx.doi.org/10.1080/0886022X.2020.1845731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7671672PMC
November 2020

The Effect of Postoperative Fluid Balance on the Occurrence and Progression of Acute Kidney Injury After Cardiac Surgery.

J Cardiothorac Vasc Anesth 2020 Oct 10. Epub 2020 Oct 10.

Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China; Shanghai Institute of Kidney Disease and Dialysis, Shanghai Laboratory of Kidney Disease and Dialysis, Shanghai Medical Center of Kidney Disease, Shanghai, People's Republic of China. Electronic address:

Objectives: In addition to the association between positive fluid balance (FB) and acute kidney injury (AKI) after cardiac surgery reported by former studies, this study examined the relationship between FB and progressive AKI.

Design: A retrospective, observational study.

Setting: University teaching, grade A tertiary hospital in Shanghai, China.

Participants: Adult patients after cardiac surgery from July-December 2016.

Interventions: Perioperative data relating to postoperative fluid intake and output were collected. AKI progression was defined as a worsening of AKI stage. FB was calculated as (fluid intake [L] - fluid output [L]/body weight [kg] × 100%).

Measurements And Main Results: The study comprised 1,522 patients. The incidences of AKI and progressive AKI were 33.1% (n = 504) and 18.1% (n = 91), respectively. There was an exponential increase between 24-hour FB and AKI occurrence, and an approximate "U"-shape association between 48-hour FB and AKI progression. Multivariate logistic regression showed that 24-hour FB ≥5% was an independent risk factor for AKI incidence (odds ratio [OR] 3.976; p < 0.001) and 48-hour FB <-5% or ≥3% was associated with an increase of AKI progression (FB <-5%, OR 7.078 [p = 0.031]; FB 3%-5%, OR 6.598 [p = 0.020]; FB ≥5%, OR 16.453 [p < 0.001]).

Conclusions: An exponential increase was found between 24-hour FB and AKI occurrence and a "U"-shape association between 48-hour FB and AKI progression. Both excessively negative and positive accumulative 48-hour FB increased the risk of AKI progression, suggesting cautious monitoring and application of fluid load in clinical practice.
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http://dx.doi.org/10.1053/j.jvca.2020.10.007DOI Listing
October 2020

Novel predictive biomarkers for acute injury superimposed on chronic kidney disease.

Nefrologia 2021 Mar-Apr;41(2):165-173. Epub 2020 Nov 4.

Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Medical Center of Kidney, Shanghai, China; Shanghai Key Laboratory of Kidney and Blood Purification, Shanghai, China. Electronic address:

Introduction And Objectives: Chronic kidney disease (CKD) is a risk factor for the development of acute kidney injury (AKI). Recent studies have revealed numerous biomarkers eligible for AKI prediction. However, the expression and performance of AKI biomarkers in acute injury superimposed on preexisting CKD (AonC) remain elusive. The aim of this study was to evaluate whether biomarkers which robustly expressed in acute kidney injury could predict acute injury based on CKD.

Materials And Methods: Mice were classified into cohorts: AKI, CKD, AonC and sham. The AonC model mice were subjected to renal bilateral ischemia/reperfusion (I/R) injury fourteen days after intraperitoneally administrated with 20mg/kg aristolochic acid. Severity of acute ischemic injury was stratified by clamping the dissected bilateral renal arteries with non-traumatic microvascular clips for 20 or 35min. The AKI mice were induced with renal bilateral I/R injury and CKD mice were crafted with 20mg/kg aristolochic acid administrated intraperitoneally. Histology, genetic and protein expression of biomarkers were measured in three cohorts.

Results: We found that serum creatinine dramatically increased in severe (sAonC) but not in moderate (mAonC) injury mice. Upregulation of Kidney injury molecule-1 (KIM-1) mRNA, tissue inhibitor of metalloproteinase-2 (TIMP-2), Syndecan-1 (SDC-1) mRNA and insulin-like growth factor binding protein-7 (IGFBP7) protein indicated the onset of mAonC. An increase in neutrophil gelatinase-associated lipocalin (NGAL), rhomboid-like protein 2 (RHBDL2), Syndecan-1 (SDC-1) mRNA and protein, and a decrease in IGFBP7 protein were associated with sAonC.

Conclusions: Our study revealed the variational expression of AKI biomarkers in AonC kidneys, and uncovered IGFBP7 protein can be used as a sensitive biomarker to predict and differentiate AonC severity. The performance of RHBDL2 and SDC-1 in predicting severe AonC was promising, providing new biomarkers for predicting AonC.
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http://dx.doi.org/10.1016/j.nefro.2020.06.007DOI Listing
November 2020

The Effect of Admission Serum Magnesium on the Acute Kidney Injury Among Patients with Malignancy.

Cancer Manag Res 2020 11;12:7199-7207. Epub 2020 Aug 11.

Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai Institute of Kidney Disease and Dialysis (SIKD), Shanghai Key Laboratory of Kidney and Blood Purification, Shanghai Medical Center of Kidney Disease, Shanghai, People's Republic of China.

Purpose: This study aimed to explore the relationship between serum magnesium (Mg) levels and incidence of acute kidney injury (AKI) in patients with malignancy.

Patients And Methods: Hospitalized patients with malignancy between October 1, 2014 and September 30, 2015 in Zhongshan Hospital were recruited. All relevant data were extracted from the electronic database.

Results: All 99,845 patients were enrolled and 16,082 eligible patients were divided into three groups according to admission serum Mg levels in this study. Among them, 2383 (14.8%) cases were diagnosed as AKI. The incidence of AKI showed a V trend with the increase of serum Mg level. The effect of low serum Mg level on the onset of AKI seems to be greater than high serum Mg level. Patients with low serum Mg level spent a longer time in the hospital than those with normal serum Mg level and high serum Mg level. Further, multivariate logistic regression model was used to assess the importance of serum Mg level to influence AKI incidence. There was a higher AKI incidence in patients with magnesium level 0.66mmol/L or less (aOR=2.438, 95% CI=1.696, 3.505).

Conclusion: Low serum Mg level might be a independent risk factor for AKI in patients with malignancy. Appropriate clinical intervention for serum Mg disorder may contribute to decreasing the incidence of AKI and the possibility of poor outcomes in cancer patients.
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http://dx.doi.org/10.2147/CMAR.S262674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431168PMC
August 2020

Prediction models for acute kidney injury in patients with gastrointestinal cancers: a real-world study based on Bayesian networks.

Ren Fail 2020 Nov;42(1):869-876

Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China.

Background: This study attempts to establish a Bayesian networks (BNs) based model for inferring the risk of AKI in gastrointestinal cancer (GI) patients, and to compare its predictive capacity with other machine learning (ML) models.

Methods: From 1 October 2014 to 30 September 2015, we recruited 6495 inpatients with GI cancers in a tertiary hospital in eastern China. Data on demographics, clinical and laboratory indicators were retrospectively extracted from the electronic medical record system. Predictors of AKI were selected in gLASSO regression, and further incorporated into BNs analysis.

Results: The incidences of AKI in patients with esophagus, stomach, and intestine cancer were 20.5%, 13.9%, and 12.5%, respectively. Through gLASSO, 11 predictors were screened out, including diabetes, cancer category, anti-tumor treatment, ALT, serum creatinine, estimated glomerular filtration rate (eGFR), serum uric acid (SUA), hypoalbuminemia, anemia, abnormal sodium, and potassium. BNs model revealed that cancer category, treatment, eGFR, and hypoalbuminemia had direct connections with AKI. Diabetes and SUA were indirectly linked to AKI through eGFR, and anemia created connections with AKI through affecting album level. Compared with other ML models, BNs model maintained a higher AUC value in both the internal and external validation (AUC: 0.823/0.790).

Conclusion: BNs model not only delineates the qualitative and quantitative relationship between AKI and its associated factors but shows the more robust generalizability in AKI prediction.
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http://dx.doi.org/10.1080/0886022X.2020.1810068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7472473PMC
November 2020

Upregulation of miR-382 contributes to renal fibrosis secondary to aristolochic acid-induced kidney injury via PTEN signaling pathway.

Cell Death Dis 2020 08 14;11(8):620. Epub 2020 Aug 14.

Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China.

Acute kidney injury (AKI) has a critical role in the development of chronic kidney disease (CKD). Building on our previous findings, we explored the role of miR-382 in facilitating the transition of AKI to CKD using the Aristolochic acid (AA) nephropathy model, which was induced by intraperitoneal injection of aristolochic acid I salt (10 or 20 mg/kg). The effects of genetic depletion, pharmacologic inhibition, or overexpression of miR-382 on the PTEN/AKT signaling pathway were examined in vivo and in vitro. Changes in renal pathology and renal epithelial polarity were evaluated. A luciferase reporter assay was performed to investigate the reciprocal suppression relationship between miR-382 and PTEN. Renal fibrosis developed 14 d after AA exposure in a dose- and time-dependent manner. Renal abundance of miR-382 was upregulated following AA treatment, while genetic depletion or pharmacological inhibition of miR-382 partially reversed renal tubulointerstitial fibrosis. Expression of PTEN, a target of miR-382, was downregulated and subsequently its downstream AKT signaling pathway was activated during AKI to CKD transition induced by AA. Inhibition of PTEN in vitro resulted in the acquisition of the EMT phenotypes. Furthermore, upregulation of miR-382 in renal epithelial cells was partially mediated by the activation of NF-kB signaling, with a substantial elevation of proinflammatory cytokines. An in vivo study revealed that either miR-382 knockdown or miR-382 knockout was pivotal for inflammatory suppression, while an in vitro experiment confirmed that upregulation of miR-382 in cultured MTEC cells under AA exposure was remarkably reversed by NF-kB siRNA. These data indicated a novel role for the NF-κB/miR-382/PTEN/AKT axis in the pathogenesis of tubulointerstitial fibrosis following AA-induced acute renal tubular epithelial injury. Targeting miR-382 may lead to a potential novel therapeutic approach for retarding the AKT to CKD transition.
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http://dx.doi.org/10.1038/s41419-020-02876-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429500PMC
August 2020

Hydrogen sulfide attenuates renal fibrosis by inducing TET-dependent DNA demethylation on Klotho promoter.

FASEB J 2020 09 30;34(9):11474-11487. Epub 2020 Jul 30.

Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China.

Hypoxia is a key pathogenetic characteristic of chronic kidney disease (CKD). Klotho has renoprotective effect and its expression is commonly suppressed in CKD patients. We showed that chronic hypoxia in unilateral ureteral obstruction model mice is associated with renal Klotho promoter methylation and expression silencing. Administration of low-dose of sodium hydrosulfide (NaHS) effectively ameliorated renal tubulointerstitial fibrosis in the mouse model by demethylating Klotho promoter and restoring its expression. Mechanistically, hypoxia microenvironment in CKD reduced cellular oxygen availability and Fe concentration, and led to impaired activity of ten-eleven translocation (TET), which is critical in maintaining Klotho promoter demethylation status. NaHS treatment greatly improved hypoxia condition, restored TET activity, reversed DNA methylation, and thus, increased Klotho expression. Our results strongly suggested that correcting hypoxia condition to restore TET activity could be a promising therapeutic strategy against CKD.
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http://dx.doi.org/10.1096/fj.201902957RRDOI Listing
September 2020

Changes in employment status prior to initiation of maintenance hemodialysis in the USA from 2006 to 2015.

Clin Kidney J 2020 Jun 14;13(3):434-441. Epub 2019 Jun 14.

Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, MI, USA.

Background: Hemodialysis (HD) patients have high unemployment rates associated with higher mortality and poor quality of life. Changes in employment status prior to dialysis initiation may predict subsequent patient outcomes. We sought to examine US national trends in employment status prior to and at HD initiation, risk factors for job loss and their association with transplantation and mortality.

Methods: Employment was defined as working full-time or part-time for 496 989 patients initiating maintenance HD from 2006 to 2015. Associations between patient and dialysis facility characteristics and employment change were analyzed using multivariable logistic regression. Cox regression was used to assess job loss with mortality and transplantation.

Results: About 26% ( = 129 622) of patients were employed 6 months prior compared with 15% ( = 75 719) at HD initiation. Employment rates 6 months prior to HD initiation decreased from 29% in 2006 to 23% in 2014. Employed patients who maintained employment increased from 57% in 2006 to 64% in 2015. Patients who were older, female, Hispanic, Black, with more comorbidities or living in low-income zip codes were less likely to maintain employment. Facility characteristics associated with employment maintenance included nonprofit status, more stations, dialysis availability after 5 p.m. and home dialysis training. Patients maintaining employment during the 6 months prior to HD had lower mortality and higher transplantation rates than patients who became unemployed.

Conclusions: Employment rates among HD patients are low and employment changes common during the 6 months prior to HD. Maintaining employment status was associated with key patient and facility characteristics, kidney transplantation and survival.
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http://dx.doi.org/10.1093/ckj/sfz077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367129PMC
June 2020

Depletion of miR-21 in dendritic cells aggravates renal ischemia-reperfusion injury.

FASEB J 2020 09 15;34(9):11729-11740. Epub 2020 Jul 15.

Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China.

Dendritic cells (DCs) play an important role in the pathophysiology of renal ischemia-reperfusion injury (IRI). The mechanisms underlying DCs phenotypic modulation and their function are not fully understood. In this study, we examined the effect of miR-21 on the phenotypic modulation of DCs in vitro and in vivo, and further investigated the impact of miR-21-overexpression DC or miR-21-deficient DC on renal IRI. We found that treatment with hypoxia/reoxygenation (H/R) suppressed miR-21 expression in bone marrow-derived dendritic cells (BMDCs), and significantly increased the percentage of mature DCs (CD11c /MHC-II /CD80 ). Using a selection of microRNA mimics, we successfully induced the upregulation of miR-21 in BMDCs, which induced immature DC phenotype and an anti-inflammatory DC response. However, deletion of miR-21 in BMDCs promoted maturation of DCs under H/R. Adoptive transfer of miR-21-overexpression BMDCs could alleviate renal IR-induced pro-inflammatory cytokines production and acute kidney injury (AKI). Mice with miR-21 deficiency in DCs subjected to renal IR showed more severe renal dysfunction and inflammatory response compared with wild-type mice. In addition, chemokine C receptor 7 (CCR7), a surface marker of mature DC, was a target gene of miR-21, and silencing of CCR7 in BMDCs led to reduced mature DCs under H/R. In conclusion, our findings highlight miR-21 as a key regulator of DCs subset phenotype and a potential therapeutic target in renal IRI.
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http://dx.doi.org/10.1096/fj.201903222RRDOI Listing
September 2020

Premature aging of circulating T cells predicts all-cause mortality in hemodialysis patients.

BMC Nephrol 2020 07 13;21(1):271. Epub 2020 Jul 13.

Department of Nephrology, Zhongshan Hospital, Fudan University, NO180, Feng'lin Road, Xuhui District, Shanghai, 200032, P.R. China.

Background: Patients with end-stage renal disease (ESRD) exhibit a premature aging phenotype of immune system, which is recently concerned as a significant factor for increased risk of various morbidities. Nevertheless, there are few dates explicating the relevancy of T cell senescence to mortality. In this study, we prospectively studied the predictive value of T cell senescence for mortality in hemodialysis patients.

Methods: Patients who had been on hemodialysis treatment for at least 6 months were enrolled. T cell senescence determined by differentiation status was evaluated by flow cytometry. Survival outcomes were estimated using the Kaplan-Meier method. Univariate and multivariate analyses were performed to evaluate the prognostic impact of T cell premature aging and other clinical factors on all-cause mortality.

Results: A total of 466 patients (277 man and 169 women) were enrolled in this study. Decreased number of naïve T cell, as the most prominent feature of T cell senescence, did not change in parallel with age in these patients. Decreased absolute count of T cell, naïve T cell, CD4 naïve T cell were independently associated with all-cause mortality. Decreased percentage of T cell and increased percentage of CD8central-memory T cell were also independently associated with all-cause mortality. After including all the T cell parameters in one regression model, only decreased count of naïve T cell was significantly associated with increased mortality in these patients.

Conclusions: Aging-associated T cell changes are aggravated in ESRD patients. For the first time, our study demonstrates that naïve T cell depletion is a strong predictor of all-cause mortality in HD patients.
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http://dx.doi.org/10.1186/s12882-020-01920-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359274PMC
July 2020

Volume-associated hemodynamic variables for prediction of cardiac surgery-associated acute kidney injury.

Clin Exp Nephrol 2020 Sep 3;24(9):798-805. Epub 2020 Jun 3.

Department of Nephrology, Zhongshan Hospital, Shanghai Medical College, Fudan University, No. 180 Fenglin Road, Shanghai, 200032, China.

Background: Delayed diagnosis of acute kidney injury (AKI) is common because the changes in renal function markers often lag injury. We aimed to find optimal non-invasive hemodynamic variables for the prediction of postoperative AKI and AKI renal replacement therapy (RRT).

Methods: The data were collected from 1,180 patients who underwent cardiac surgery in our hospital between March 2015 and Feb 2016. Postoperative central venous pressure (CVP), mean arterial pressure (MAP), heart rate, PaO, and PaCO on ICU admission and daily fluid input and output (calculated as 24 h PFO) were monitored and compared between AKI vs. non-AKI and RRT vs non-RRT cases.

Results: The AKI and AKI-RRT incidences were 36.7% (n = 433) and 1.2% (n = 14). Low cardiac output syndromes (LCOSs) occurred significantly more in AKI and RRT than in non-AKI or non-RRT groups (13.2% vs. 3.9%, P < 0.01; 42.9% vs. 7.1%, P < 0.01). CVP on ICU admission was significantly higher in AKI and RRT than in non-AKI and non-RRT groups (11.5 vs. 9.0 mmHg, P < 0.01; 13.3 vs. 9.9 mmHg, P < 0.01). 24 h PFO in AKI and RRT cases were significantly higher than in non-AKI or non-RRT patients (1.6% vs. 0.9%, P < 0.01; 3.9% vs. 0.8%, P < 0.01). The areas under the ROC curves to predict postoperative AKI by CVP on ICU admission (> 11 mmHg) + LCOS + 24 h PFO (> 5%) and to predict AKI-RRT by CVP on ICU admission (> 13 mmHg) + LCOS + 24 h PFO (> 5%) were 0.763 and 0.886, respectively.

Conclusion: The volume-associated hemodynamic variables, including CVP on ICU admission, LCOS, and 24 h PFO after surgery could predict postoperative AKI and AKI-RRT.
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http://dx.doi.org/10.1007/s10157-020-01908-6DOI Listing
September 2020

Transcriptome Profiling Reveals Indoxyl Sulfate Should Be Culpable of Impaired T Cell Function in Chronic Kidney Disease.

Front Med (Lausanne) 2020 6;7:178. Epub 2020 May 6.

Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China.

Chronic inflammation and immune system dysfunction have been evaluated as major factors in the pathogenesis of chronic kidney disease (CKD), contributing to the high mortality rates observed in these populations. Uremic toxins seem to be the potential "missing link." Indoxyl sulfate (IS) is one of the protein-bound renal toxins. It participates in multiple pathologies of CKD complications, yet its effect on immune cell has not been studied. This study aimed to explore the genome-wide expression profile in human peripheral blood T cells under stimulation by IS. In this study, we employed RNA-sequencing transcriptome profiling to identify differentially expressed genes (DEGs) responding to IS stimulation in human peripheral T cells . Flow cytometry and western blot were used to verify the discovery in RNA-sequencing analysis. Our results yielded a total of 5129 DEGs that were at least twofold up-regulated or down-regulated significantly by IS stimulation and half of them were concentration-specific. Analysis of T cell functional markers revealed a quite different transcription profile under various IS concentration. Transcription factors analysis showed the similar pattern. Aryl hydrocarbon receptor (AhR) target genes CYP1A1, CYP1B1, NQO1, and AhRR were up-regulated by IS stimulation. Pro-inflammatory genes TNF-α and IFN-γ were up-regulated as verified by flow cytometry analysis. DNA damage was induced by IS stimulation as confirmed by elevated protein level of p-ATM, p-ATR, p-BRCA1, and p-p53 in T cells. The toxicity of IS to T cells could be an important source of chronic inflammation in CKD patients. As an endogenous ligand of AhR, IS may influence multiple biological functions of T cells including inflammatory response and cell cycle regulation. Further researches are required to promulgate the underling mechanism and explore effective method of reserving T cell function in CKD.
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http://dx.doi.org/10.3389/fmed.2020.00178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218060PMC
May 2020