Publications by authors named "Xiangmei Chen"

400 Publications

Isonicotinylation is a histone mark induced by the anti-tuberculosis first-line drug isoniazid.

Nat Commun 2021 Sep 20;12(1):5548. Epub 2021 Sep 20.

Program for Cancer and Cell Biology, Department of Human Anatomy, Histology and Embryology, PKU International Cancer Institute, MOE Key Laboratory of Carcinogenesis and Translational Research and State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing, PR China.

Isoniazid (INH) is a first-line anti-tuberculosis drug used for nearly 70 years. However, the mechanism underlying the side effects of INH has remained elusive. Here, we report that INH and its metabolites induce a post-translational modification (PTM) of histones, lysine isonicotinylation (K), also called 4-picolinylation, in cells and mice. INH promotes the biosynthesis of isonicotinyl-CoA (Inic-CoA), a co-factor of intracellular isonicotinylation. Mass spectrometry reveals 26 K sites in histones in HepG2 cells. Acetyltransferases CREB-binding protein (CBP) and P300 catalyse histone K, while histone deacetylase HDAC3 functions as a deisonicotinylase. Notably, MNase sensitivity assay and RNA-seq analysis show that histone K relaxes chromatin structure and promotes gene transcription. INH-mediated histone K upregulates PIK3R1 gene expression and activates the PI3K/Akt/mTOR signalling pathway in liver cancer cells, linking INH to tumourigenicity in the liver. We demonstrate that K is a histone acylation mark with a pyridine ring, which may have broad biological effects. Therefore, INH-induced isonicotinylation potentially accounts for the side effects in patients taking INH long-term for anti-tuberculosis therapy, and this modification may increase the risk of cancer in humans.
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http://dx.doi.org/10.1038/s41467-021-25867-yDOI Listing
September 2021

Severe postoperative hyperbilirubinemia in congenital heart disease.

Open Med (Wars) 2021 31;16(1):1276-1285. Epub 2021 Aug 31.

Department of Nephrology, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, Shaanxi, China.

Purpose: The purpose of our present study was to explore the characteristics and outcomes of congenital heart disease (CHD) patients with severe postoperative hyperbilirubinemia.

Methods: All patients who underwent cardiopulmonary bypass surgical treatment for CHD and had severe postoperative hyperbilirubinemia (total bilirubin [TB] ≥85.5 μmol/L) in our center between January 2015 and December 2018 were retrospectively screened. Univariate and multivariate analyses were employed to identify risk factors for the study endpoints, including postoperative acute kidney injury (AKI), in-hospital mortality, and long-term mortality.

Results: After screening, 86 patients were included in our present study. In-hospital mortality was 10.9%. Fifty-one (59.3%) patients experienced AKI, and four (4.7%) patients received continuous renal replacement therapy. Multivariate analysis identified that the peak TB concentration ( = 0.002) and duration of mechanical ventilation ( = 0.008) were independent risk factors for in-hospital mortality, and stage 3 AKI was an independent risk factor for long-term mortality. The optimal cutoff value for peak TB concentration was 125.9 μmol/L. Patients with a postoperative TB level ≥125.9 μmol/L had worse long-term survival.

Conclusion: Hyperbilirubinemia was a common complication after CHD surgery. CHD patients with severe postoperative hyperbilirubinemia ≥125.9 μmol/L and AKI had a higher risk of mortality.
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http://dx.doi.org/10.1515/med-2021-0316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409460PMC
August 2021

Safety and Efficacy of Roxadustat for Anemia in Patients With Chronic Kidney Disease: A Meta-Analysis and Trial Sequential Analysis.

Front Med (Lausanne) 2021 31;8:724456. Epub 2021 Aug 31.

Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, China.

Roxadustat, a hypoxia-inducible factor prolyl-hydroxylase inhibitor (HIF-PHI), has been used to treat anemia in patients with chronic kidney disease (CKD). However, its safety and efficacy remain controversial. The PubMed, EMBASE, Science Citation Index, Cochrane Central Register of Controlled Trials, and Clinical Trial Registries databases were searched for relevant studies published up to April 2021. We identified randomized controlled trials (RCTs) comparing roxadustat with placebo or erythropoiesis-stimulating agents (ESAs) in anemia patients with CKD with or without dialysis. Eleven studies including 6,631 patients met the inclusion criteria. In non-dialysis-dependent (NDD-) and dialysis-dependent (DD-) CKD patients, the total adverse events were not significantly different between the roxadustat and control (placebo for NDD-CKD patients and ESA for DD-CKD patients) groups [relative risk (RR) = 1.02, 95% confidence interval (CI) = 1.00, 1.04, = 0.08, and RR = 1.22, 95% CI = 0.91, 1.64, = 0.18, respectively], and the trial sequential analysis (TSA) confirmed the result in the NDD-CKD groups. No significant differences in hyperkalemia and infection incidences were found between roxadustat and placebo in the DD-CKD groups. The pooled results showed that roxadustat significantly increased the hemoglobin response rate compared with placebo in the NDD-CKD group and had an effect similar to that of ESA in the DD-CKD group. However, iron metabolism parameters did not seem to be obviously optimized by roxadustat. Roxadustat can be safely used in CKD patients. Oral roxadustat was more effective than placebo as a therapy for anemia in NDD-CKD patients and non-inferior to ESA in correcting anemia in DD-CKD patients. However, additional clinical trials are still needed to further prove whether roxadustat can optimize iron metabolism.
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http://dx.doi.org/10.3389/fmed.2021.724456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8438137PMC
August 2021

Metabolic nuclear receptors coordinate energy metabolism to regulate Sox9 hepatocyte fate.

iScience 2021 Sep 19;24(9):103003. Epub 2021 Aug 19.

College of Veterinary Medicine/Bio-medical Center, Huazhong Agricultural University, Wuhan, Hu Bei 430070, China.

Recent research has indicated the adult liver Sox9 cells located in the portal triads contribute to the physiological maintenance of liver mass and injury repair. However, the physiology and pathology regulation mechanisms of adult liver Sox9 cells remain unknown. Here, PPARα and FXR bound to the shared site in Sox9 promoter with opposite transcriptional outputs. PPARα activation enhanced the fatty acid β-oxidation, oxidative phosphorylation (OXPHOS), and adenosine triphosphate (ATP) production, thus promoting proliferation and differentiation of Sox9 hepatocytes along periportal (PP)-perivenous (PV) axis. However, FXR activation increased glycolysis but decreased OXPHOS and ATP production, therefore preventing proliferation of Sox9 hepatocytes along PP-PV axis by promoting Sox9 hepatocyte self-renewal. Our research indicates that metabolic nuclear receptors play critical roles in liver progenitor Sox9 hepatocyte homeostasis to initiate or terminate liver injury-induced cell proliferation and differentiation, suggesting that PPARα and FXR are potential therapeutic targets for modulating liver regeneration.
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http://dx.doi.org/10.1016/j.isci.2021.103003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8417399PMC
September 2021

Pacbio Sequencing of PLC/PRF/5 Cell Line and Clearance of HBV Integration Through CRISPR/Cas-9 System.

Front Mol Biosci 2021 17;8:676957. Epub 2021 Aug 17.

Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.

The integration of HBV DNA is one of the carcinogenic mechanisms of HBV. The clearance of HBV integration in hepatocyte is of great significance to cure chronic HBV infection and thereby prevent the occurrence of HBV-related hepatocellular carcinoma (HCC). However, the low throughput of traditional methods, such as Alu-PCR, results in low detecting sensitivity of HBV integration. Although the second-generation sequencing can obtain a large amount of sequencing data, but the sequencing fragments are extremely short, so it cannot fully explore the characteristics of HBV integration. In this study, we used the third-generation sequencing technology owning advantages both in sequencing length and in sequencing depth to analyze the HBV integration characteristics in PLC/PRF/5 cells comprehensively. A total of 4,142,311 cleaning reads was obtained, with an average length of 18,775.6 bp, of which 84 reads were fusion fragments of the HBV DNA and human genome. These 84 fragments located in seven chromosomes, including chr3, chr4, chr8, chr12, chr13, chr16, and chr17. We observed lots of DNA rearrangement both in the human genome and in HBV DNA fragments surrounding the HBV integration site, indicating the genome instability causing by HBV integration. By analyzing HBV integrated fragments of PLC/PRF/5 cells that can potentially express HBsAg, we selected three combinations of sgRNAs targeting the integrated fragments to knock them out with CRISPR/Cas9 system. We found that the sgRNA combinations could significantly decrease the level of HBsAg in the supernatant of PLC/PRF/5 cells, while accelerated cell proliferation. This study proved the effectiveness of third-generation sequencing to detect HBV integration, and provide a potential strategy to reach HBsAg clearance for chronic HBV infection patients, but the knock-out of HBV integration from human genome by CRISPR/Cas9 system may have a potential of carcinogenic risk.
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http://dx.doi.org/10.3389/fmolb.2021.676957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416172PMC
August 2021

The weak correlation between serum vitamin levels and chronic kidney disease in hospitalized patients: a cross-sectional study.

BMC Nephrol 2021 Aug 26;22(1):292. Epub 2021 Aug 26.

Department of Nephrology, State Key Laboratory of Kidney Diseases, First Medical Center of Chinese People's Liberation Army General Hospital, Chinese People's Liberation Army Institute of Nephrology, National Clinical Research Center for Kidney Diseases, Fuxing Road 28, 100853, Beijing, China.

Background: Chronic kidney disease (CKD) has become a global public health problem. Accumulating evidence suggested that vitamins play important roles in the progression of CKD.

Methods: A cross-sectional study was conducted to investigate the vitamin status of patients with CKD at stage 1-5. The serum concentrations of 9 vitamins, vitamin A, B1, B2, B6, B9, B12, C, D, and E were measured by electroanalytical method with a Multi-Vitamin Analyzer. Pearson correlation and multiple linear regression between serum level of vitamins were analyzed.

Results: The median levels of vitamin A, B1, B2, B6, B9, B12, C and E were within the reference ranges or on the borderline. Vitamin D deficiency was found in all patients. Weak correlation was found between vitamin A or vitamin D and estimated glomerular filtration rate (eGFR). The Pearson correlation coefficient were - 0.21766 and 0.19752, respectively. Hypertension, diabetes mellitus, and atherosclerosis were the major comorbidities.

Conclusions: For the first time, the serum levels of 9 vitamins were measured simultaneously in patients with CKD at different stages. Vitamin D deficiency was found in all patients. Weak correlation between vitamin A or vitamin D and eGFR was found.
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http://dx.doi.org/10.1186/s12882-021-02498-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8393712PMC
August 2021

Meta-Analysis of Renal Replacement Therapy for Burn Patients: Incidence Rate, Mortality, and Renal Outcome.

Front Med (Lausanne) 2021 9;8:708533. Epub 2021 Aug 9.

State Key Laboratory of Kidney Diseases, Department of Nephrology, National Clinical Research Center for Kidney Diseases, Chinese People's Liberation Army Institute of Nephrology, Chinese People's Liberation Army General Hospital, Beijing, China.

Renal replacement therapy (RRT) was often needed by some severe burn patients with acute kidney injury (AKI). The primary aim of this study was to review incidence rate and mortality of RRT in severe burn patients. Second aims were to review RRT complications and renal outcome. We searched multiple databases for studies published between 1 January 1960 and 31 December 2019. Studies about adult populations with burn injury, providing epidemiologic data on prevalence or mortality of RRT, were included. A total of selected 57 studies, including 27,437 patients were enrolled in our analysis. The prevalence rates of RRT were 8.34% (95% CI 7.18-9.5%) in all burn patients and 37.05% (95% CI 29.85-44.24%) in AKI patients. The mortality of all burn patients with RRT was 65.52% (95% CI 58.41-72.64%). The prevalence rates of RRT in sample size≥100 group were 6.86% (95% CI 5.70-8.03%), which was lower than that of <100 group (17.61%, 95% CI 13.39-21.82%). With the increase of TBSA, the prevalence of RRT may have the increasing trend. The prevalence rates of RRT in Asian group was 12.75% (95% CI 9.50-16.00%), which was higher than that of European (10.45%, 95% CI 7.30-13.61%) and North America group (5.61%, 95% CI 4.27-6.95%). The prevalence rates of RRT in 2010-2019 group was 12.22% (95% CI 10.09-14.35%), which was higher than that of 2009-2000 group (5.17%, 95% CI 2.88-7.46%). The prevalence rates of RRT in 1989 and before group was the lowest, which was 1.56% (95% CI 0-3.68%). However, there was no significant correlation between the year of publication and the mortality of burn patients with RRT. Dialysis-requiring AKI in burn patients could increases the risk of chronic kidney disease progression and end-stage renal disease. About 35% of RRT patients need to maintain haemodialysis temporarily, even if they survive and leave hospital. The prevalence rate of RRT is about 6-8%; approximately, one-third of burn patients with AKI need RRT. The prevalence rate of RRT increased over time, but the mortality did not change. The prevalence rates of RRT in Asian group was higher than that of European and North America group.
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http://dx.doi.org/10.3389/fmed.2021.708533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8381047PMC
August 2021

Establishment of PLAFMCi005-A induced pluripotent stem cells derived from PBMC from a patient with renal cysts and diabetes syndrome.

Stem Cell Res 2021 Aug 2;55:102485. Epub 2021 Aug 2.

Department of Nephrology, The First Medical Center, Chinese PLA General Hospital, Medical School of Chinese PLA, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing 100853, China; School of Medicine, Nankai University, Tianjin 300071, China. Electronic address:

Renal cysts and diabetes syndrome (RCAD) is caused by gene mutations in hepatocyte nuclear factor 1-β (HNF1B), but the underlying molecular mechanism is still unclear. This study established PLAFMCi005-A human induced pluripotent stem cells (iPSCs) by reprogramming peripheral blood mononuclear cells (PBMCs) from an RCAD patient. PLAFMCi005-A has differentiation potential and can be used to investigate the pathogenesis of RCAD caused by HNF1B gene mutations, thus promoting the development of related drugs.
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http://dx.doi.org/10.1016/j.scr.2021.102485DOI Listing
August 2021

Association between higher serum uric acid levels within the normal physiological range and changes of lumbar spine bone mineral density in healthy Chinese postmenopausal women: a longitudinal follow-up study.

Menopause 2021 Aug 2. Epub 2021 Aug 2.

Department of Gerontology and Geriatrics, Shengjing Hospital of China Medical University, Shenyang, China Department of Kidney, General Hospital of Chinese People's Liberation Army, Beijing, China.

Objectives: The aim of this study was to investigate whether higher serum uric acid (SUA) levels within the physiological range were associated with changes in lumbar spine bone mineral density (LBMD) in postmenopausal women without existing lumbar spine osteoporosis after a longitudinal follow-up of 3.09 years, and to further confirm the relationship between SUA and bone mineral density (BMD) in other sites such as femoral neck, total hip, and trochanter at follow-up.

Methods: A longitudinal study of 175 healthy postmenopausal women without osteoporosis was conducted in Shenyang, China. BMD of the lumbar spine, femoral neck, total hip, and trochanter were measured using dual-energy x-ray absorptiometry at each visit. Pearson's correlation analysis and regression analyses were performed to determine any associations.

Results: There were positive correlations between baseline SUA and BMD of the lumbar spine (P = 0.03), total hip (P = 0.04), and trochanter (P = 0.04). Moreover, higher baseline SUA levels were independently associated with LBMD decline and the odds ratio of the baseline SUA of the third quartile group was 0.12 (95% confidence interval, 0.02-0.70, P < 0.05), with P = 0.23 for the trend in baseline SUA when compared with participants in the lowest, first quartile group after adjustment for many potential confounding variables.

Conclusions: Higher SUA levels within the normal physiological range were independently associated with decreased LBMD, and SUA levels were positively related to the BMD of the lumbar spine, total hip, and trochanter in healthy Chinese postmenopausal women.
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http://dx.doi.org/10.1097/GME.0000000000001821DOI Listing
August 2021

A global survey of alternative splicing of HBV transcriptome using long-read sequencing.

J Hepatol 2021 Jul 28. Epub 2021 Jul 28.

Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China. Electronic address:

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http://dx.doi.org/10.1016/j.jhep.2021.07.023DOI Listing
July 2021

RNA Methylation in Systemic Lupus Erythematosus.

Front Cell Dev Biol 2021 7;9:696559. Epub 2021 Jul 7.

Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing, China.

Systemic lupus erythematosus (SLE) is an autoimmune disease with complicated clinical manifestations. Although our understanding of the pathogenesis of SLE has greatly improved, the understanding of the pathogenic mechanisms of SLE is still limited by disease heterogeneity, and targeted therapy is still unavailable. Substantial evidence shows that RNA methylation plays a vital role in the mechanisms of the immune response, prompting speculation that it might also be related to the occurrence and development of SLE. RNA methylation has been a hot topic in the field of epigenetics in recent years. In addition to revealing the modification process, relevant studies have tried to explore the relationship between RNA methylation and the occurrence and development of various diseases. At present, some studies have provided evidence of a relationship between RNA methylation and SLE pathogenesis, but in-depth research and analysis are lacking. This review will start by describing the specific mechanism of RNA methylation and its relationship with the immune response to propose an association between RNA methylation and SLE pathogenesis based on existing studies and then discuss the future direction of this field.
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http://dx.doi.org/10.3389/fcell.2021.696559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292951PMC
July 2021

LncRNA-HOTAIR promotes endothelial cell pyroptosis by regulating the miR-22/NLRP3 axis in hyperuricaemia.

J Cell Mol Med 2021 Sep 22;25(17):8504-8521. Epub 2021 Jul 22.

Department of Nephrology, Chinese PLA General Hospital, Medical School of Chinese PLA, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases, Beijing, China.

Long non-coding RNA (lncRNA) plays an important role in the renal inflammatory response caused by hyperuricaemia. However, the underlying molecular mechanisms through which lncRNA is involved in endothelial injury induced by hyperuricaemia remain unclear. In this study, we investigated the regulatory role of lncRNA-HOTAIR in high concentration of uric acid (HUA)-induced renal injury. We established hyperuricaemia mouse model and an in vitro uric acid (UA)-induced human umbilical vein endothelial cell (HUVEC) injury model. In HUA-treated HUVECs and hyperuricaemia mice, we observed increased HOTAIR and decreased miR-22 expression. The expression of pyroptosis-associated protein (NLRP3, Caspase-1, GSDMD-N, GSDMD-FL) was increased. The release of LDH, IL-1β and IL-18 in cell supernatants and the sera of model mice was also increased. The proliferation of HUVECs stimulated by HUA was significantly inhibited, and the number of TUNEL-positive cells in hyperuricaemia mouse kidney was increased. Bioinformatics analysis and luciferase reporter and RIP assays confirmed that HOTAIR promoted NLRP3 inflammasome activation by competitively binding miR-22. In gain- or loss-of-function experiments, we found that HOTAIR and NLRP3 overexpression or miR-22 knock down activated the NLRP3 inflammasome and promoted pyroptosis in HUA-treated HUVECs, while NLRP3 and HOTAIR knockdown or a miR-22 mimic exerted the opposite effects. Furthermore, in vivo experiments validated that HOTAIR knockdown alleviated renal inflammation in hyperuricaemia mice. In conclusion, we demonstrated that in hyperuricaemia, lncRNA-HOTAIR promotes endothelial cell pyroptosis by competitively binding miR-22 to regulate NLRP3 expression.
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http://dx.doi.org/10.1111/jcmm.16812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419175PMC
September 2021

Expression characteristics of interferon-stimulated genes and possible regulatory mechanisms in lupus patients using transcriptomics analyses.

EBioMedicine 2021 Aug 17;70:103477. Epub 2021 Jul 17.

Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, 28 Fuxing Road, Haidian District, Beijing 100853, China. Electronic address:

Background: Type I interferon signature is one of the most important features of systemic lupus erythematosus (SLE), which indicates an active immune response to antigen invasion. Characteristics of type I interferon-stimulated genes (ISGs) in SLE patients have not been well described thus far.

Methods: We analyzed 35,842 cells of PBMC single-cell RNA sequencing data of five SLE patients and three healthy controls. Thereafter, 178 type I ISGs among DEGs of all cell clusters were screened based on the Interferome Database and AUCell package was used for ISGs activity calculation. To determine whether common ISG features exist in PBMCs and kidneys of patients with SLE, we analyzed kidney transcriptomic data from patients with lupus nephritis (LN) from the GEO database. MRL/lpr mice model were used to verify our findings.

Findings: We found that monocytes, B cells, dendritic cells, and granulocytes were significantly increased in SLE patients, while subsets of T cells were significantly decreased. Neutrophils and low-density granulocytes (LDGs) exhibited the highest ISG activity. GO and pathway enrichment analyses showed that DEGs focused on leukocyte activation, cell secretion, and pathogen infection. Thirty-one common ISGs were found expressed in both PBMCs and kidneys; these ISGs were also most active in neutrophils and LDGs. Transcription factors including PLSCR1, TCF4, IRF9 and STAT1 were found to be associated to ISGs expression. Consistently, we found granulocyte infiltration in the kidneys of MRL/lpr mice. Granulocyte inhibitor Avacopan reduced granulocyte infiltration and reversed renal conditions in MRL/lpr mice.

Interpretation: This study shows for the first time, the use of the AUCell method to describe ISG activity of granulocytes in SLE patients. Moreover, Avacopan may serve as a granulocyte inhibitor for treatment of lupus patients in the future.

Funding: None.
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http://dx.doi.org/10.1016/j.ebiom.2021.103477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8318865PMC
August 2021

The incidence, risk factors, and prognosis of postoperative hyperbilirubinemia after cardiac surgery: a systematic review and meta-analysis.

Ann Palliat Med 2021 Jul 30;10(7):7247-7257. Epub 2021 Jun 30.

Department of Nephrology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China; State Key Laboratory of Kidney Disease, Department of Nephrology, Chinese People's Liberation Army General Hospital and Military Medical Postgraduate College, Beijing, China.

Background: The purpose of the present systematic review was to evaluate the incidence, risk factors, and outcome of hyperbilirubinemia after cardiac surgery.

Methods: The Population, Interventions, Comparators, Outcomes, and Study design (PICOS) framework was employed to develop the search strategy, and the findings are reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. PubMed, Embase, and the Cochrane Library were systematically searched for studies that provided data on the incidence, risk factors, and outcomes of hyperbilirubinemia in cardiac surgery patients from January 1960 to May 2020. Publication bias was graphically explored through funnel plots, and the Newcastle-Ottawa quality assessment scale (NOS) was used to evaluate the quality of the included studies.

Results: Ten studies with 6,100 patients were included in our systematic review. The pooled incidence of hyperbilirubinemia was 23% [95% confidence interval (CI), 0.13-0.32]. Preoperative factors, including right atrial pressure [mean difference (MD), 4.65; 95% CI, 4.43-4.88], total bilirubin (TB) concentration (MD, 0.72; 95% CI, 0.65-0.79), alkaline phosphatase (MD, 27.38; 95% CI, 12.94-41.82), and alanine aminotransferase (MD, 12.02; 95% CI, 10.73-13.31), and intraoperative factors, including cardiopulmonary bypass (CPB) time (MD, 1.57; 95% CI, 0.52-2.63), aortic cross-clamping (ACC) time (MD, 11.82; 95% CI, 9.50-14.14), and the amount of blood transfused (MD, 3.77; 95% CI, 0.68-6.85), were the most robust risk factors for hyperbilirubinemia after cardiac surgery. Additionally, postoperative hyperbilirubinemia was associated with increased in-hospital mortality [odds ratio (OR), 9.9; 95% CI, 5.00-19.60, P<0.0001].

Discussion: Hyperbilirubinemia was common and was associated with increased in-hospital mortality. Preoperative high right atrial pressure, high TB concentration, prolonged CPB and ACC time, and a large amount of blood transfused were the commonly observed risk factors for postoperative hyperbilirubinemia in cardiac surgery patients. Addressing these risk factors may be helpful to lower the occurrence of postoperative hyperbilirubinemia.
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http://dx.doi.org/10.21037/apm-21-410DOI Listing
July 2021

Embryonic stem cell-derived extracellular vesicles promote the recovery of kidney injury.

Stem Cell Res Ther 2021 07 2;12(1):379. Epub 2021 Jul 2.

School of Medicine, Nankai University, Tianjin, 300071, China.

Background: Embryonic stem cell-derived extracellular vesicles (ESC-EVs) possess therapeutic potential for a variety of diseases and are considered as an alternative of ES cells. Acute kidney injury (AKI) is a common acute and severe disease in clinical practice, which seriously threatens human life and health. However, the roles and mechanisms of ESC-EVs on AKI remain unclear.

Methods: In this study, we evaluated the effects of ESC-EVs on physiological repair and pathological repair using murine ischemia-reperfusion injury-induced AKI model, the potential mechanisms of which were next investigated. EVs were isolated from ESCs and EVs derived from mouse fibroblasts as therapeutic controls. We then investigated whether ESC-EVs can restore the structure and function of the damaged kidney by promoting physiological repair and inhibiting the pathological repair process after AKI in vivo and in vitro.

Results: We found that ESC-EVs significantly promoted the recovery of the structure and function of the damaged kidney. ESC-EVs increased the proliferation of renal tubular epithelial cells, facilitated renal angiogenesis, inhibited the progression of renal fibrosis, and rescued DNA damage caused by ischemia and reperfusion after AKI. Finally, we found that ESC-EVs play a therapeutic effect by activating Sox9 cells.

Conclusions: ESC-EVs significantly promote the physiological repair and inhibit the pathological repair after AKI, enabling restoration of the structure and function of the damaged kidney. This strategy might emerge as a novel therapeutic strategy for ESC clinical application.
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http://dx.doi.org/10.1186/s13287-021-02460-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8254253PMC
July 2021

Exogenous Biological Renal Support Improves Kidney Function in Mice With Rhabdomyolysis-Induced Acute Kidney Injury.

Front Med (Lausanne) 2021 28;8:655787. Epub 2021 May 28.

State Key Laboratory of Kidney Diseases, Department of Nephrology, National Clinical Research Center for Kidney Diseases, Chinese People's Liberation Army (PLA) Institute of Nephrology, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China.

Rhabdomyolysis (RM) is a clinical syndrome characterized by breakdown of skeletal muscle fibers and release of their contents into the circulation. Myoglobin-induced acute kidney injury (AKI) is one of the most severe complications of RM. Based on our previous research, exogenous biological renal support alleviates renal ischemia-reperfusion injury in elderly mice. This study aimed to determine whether exogenous biological renal support promotes renal recovery from RM-induced AKI and to preliminarily explore the mechanisms involved. A parabiosis animal model was established to investigate the effects of exogenous biological renal support on RM-induced AKI. Mice were divided into three groups: the control group (in which mice were injected with sterile saline), the RM group (in which mice were injected with 8 mL/kg glycerol), and the parabiosis + RM group (in which recipient mice were injected with glycerol 3 weeks after parabiosis model establishment). Blood samples and kidney tissue were collected for further processing 48 h after RM induction. Bioinformatics analysis was conducted via Gene Ontology analysis, Kyoto Encyclopedia of Genes and Genomes pathway analysis, functional enrichment analysis, and clustering analysis. No mice died within 48 h after the procedure. Exogenous biological renal support attenuated the histological and functional deterioration in mice with RM-induced AKI. Bioinformatics analysis identified key pathways and proteins involved in this process. We further demonstrated that exogenous biological renal support ameliorated AKI through multiple mechanisms, including by suppressing the complement system; attenuating oxidative stress, inflammation, and cell death; and increasing proliferation. Exogenous biological renal support provided by parabiosis can improve renal function in RM-induced AKI by suppressing the complement system; decreasing oxidative stress, inflammation, and cell death; and promoting tubular cell proliferation. Our study provides basic research evidence for the use of bioartificial kidneys to treat RM-induced AKI.
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http://dx.doi.org/10.3389/fmed.2021.655787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8193099PMC
May 2021

Genetic analysis of gene and diagnostic process in patients with Gitelman syndrome.

Clin Nephrol 2021 Sep;96(3):165-174

As the most frequent inherited tubulopathy, Gitelman syndrome (GS), has an incidence that has increased worldwide. The distribution of gene mutation hotspots deserves exploration. In addition, GS is not a benign syndrome; however, the diagnostic process of GS has not yet been completely detailed.

Materials And Methods: We report two cases of GS pedigrees involving two previously unreported mutations, c. 676G>A, p. A226T and c. 421G>A, p. G141R, in the gene and reviewed relevant literature. We searched the literature for nucleotide of in PubMed and other databases as of April 20, 2020.

Results: A total of 1,794 detected mutated alleles in 939 patients worldwide were included in this study. Splicing mutations and p. Gly741Arg were mutation hotspots in a European population. P. Leu858His and p. Thr60Met were mutation hotspots in an Asian population. P. Leu858His and p. Thr180Lys were considered mutation hotspots in the Japanese population, while p. Thr60Met and p. Asp486Asn were considered mutation hotspots in the Chinese population.

Conclusion: Our results identified two novel mutation sites (c. 676G>A, p. A226T and c. 421G>A, p. G141R), if their pathogenicity was determined this could contribute to the enrichment of database resources on GS. Our study has compiled the most comprehensive gene mutation database in the world thus far to reveal that different regions have different mutation hotspots in SLC12A3. Moreover, the establishment of a diagnostic process for GS has important implications for confirmed cases.
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http://dx.doi.org/10.5414/CN110425DOI Listing
September 2021

Activated mesangial cells induce glomerular endothelial cells proliferation in rat anti-Thy-1 nephritis through VEGFA/VEGFR2 and Angpt2/Tie2 pathway.

Cell Prolif 2021 Jun 13;54(6):e13055. Epub 2021 May 13.

Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing, China.

Objectives: We aimed to investigate the underlying mechanism of endothelial cells (ECs) proliferation in anti-Thy-1 nephritis.

Materials And Methods: We established anti-Thy-1 nephritis and co-culture system to explore the underlying mechanism of ECs proliferation in vivo and in vitro. EdU assay kit was used for measuring cell proliferation. Immunohistochemical staining and immunofluorescence staining were used to detect protein expression. ELISA was used to measure the concentration of protein in serum and medium. RT-qPCR and Western blot were used to qualify the mRNA and protein expression. siRNA was used to knock down specific protein expression.

Results: In anti-Thy-1 nephritis, ECs proliferation was associated with mesangial cells (MCs)-derived vascular endothelial growth factor A (VEGFA) and ECs-derived angiopoietin2 (Angpt2). In vitro co-culture system activated MCs-expressed VEGFA to promote vascular endothelial growth factor receptor2 (VEGFR2) activation, Angpt2 expression and ECs proliferation, but inhibit TEK tyrosine kinase (Tie2) phosphorylation. MCs-derived VEGFA stimulated Angpt2 expression in ECs, which inhibited Tie2 phosphorylation and promoted ECs proliferation. And decline of Tie2 phosphorylation induced ECs proliferation. In anti-Thy-1 nephritis, promoting Tie2 phosphorylation could alleviate ECs proliferation.

Conclusions: Our study showed that activated MCs promoted ECs proliferation through VEGFA/VEGFR2 and Angpt2/Tie2 pathway in experimental mesangial proliferative glomerulonephritis (MPGN) and in vitro co-culture system. And enhancing Tie2 phosphorylation could alleviate ECs proliferation, which will provide a new idea for MPGN treatment.
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http://dx.doi.org/10.1111/cpr.13055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168418PMC
June 2021

Krϋppel-like factor 15 suppresses renal glomerular mesangial cell proliferation via enhancing P53 SUMO1 conjugation.

J Cell Mol Med 2021 06 4;25(12):5691-5706. Epub 2021 May 4.

Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases, Chinese PLA Institute of Nephrology, Chinese PLA General Hospital, Beijing, China.

Mesangial cell (MC) proliferation is a key pathological feature in a number of common human renal diseases, including mesangial proliferative nephritis and diabetic nephropathies. Knowledge of MC responses to pathological stimuli is crucial to the understanding of these disease processes. We previously determined that Krϋppel-like factor 15 (KLF15), a kidney-enriched zinc-finger transcription factor, was required for inhibition of MC proliferation. In the present study, we investigated the direct target gene and the underlying mechanism by which KLF15 regulated mesangial proliferation. First, we screened small ubiquitin-related modifier 1 (SUMO1) as the direct transcriptional target of KLF15 and validated this finding with ChIP-PCR and luciferase assays. Furthermore, we demonstrated that overexpressing KLF15 or SUMO1 enhanced the stability of P53, which blocked the cell cycle of human renal MCs (HRMCs) and therefore abolished cell proliferation. Conversely, knockdown of SUMO1 in HRMCs, even those overexpressed with KLF15, could not inhibit HRMC proliferation rates and increase SUMOylation of P53. Finally, the results showed that the levels of SUMOylated P53 in the kidney cortices of anti-Thy 1 model rats were decreased during proliferation periods. These findings reveal the critical mechanism by which KLF15 targets SUMO1 to mediate the proliferation of MCs.
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http://dx.doi.org/10.1111/jcmm.16583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184688PMC
June 2021

Ultrasound enhances the therapeutic potential of mesenchymal stem cells wrapped in greater omentum for aristolochic acid nephropathy.

Stem Cell Res Ther 2021 05 3;12(1):261. Epub 2021 May 3.

Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center of Kidney Diseases, Beijing, 100853, China.

Background: Mesenchymal stem cells (MSCs) have been reported to promote regeneration in both subjects with acute kidney injury (AKI) and chronic kidney disease (CKD), but their efficacy remains limited, probably because most of the cells accumulate in the lungs, liver, and spleen after an intravenous infusion. Therefore, ultrasound-guided administration of MSCs represents a possible approach to solve this problem. The greater omentum is used to promote cell survival due to its rich vasculature. We hypothesized that ultrasound-guided administration of MSCs combined with greater omentum might be more curative than currently available approaches.

Methods: In this study, we established an aristolochic acid nephropathy (AAN) model by intraperitoneally administering aristolochic acid I sodium salt (AA-I) at a dose of 5 mg/kg body weight on alternate days for 4 weeks. Subsequently, a laparotomy was performed, and the left kidney from which the capsule had been removed was wrapped with the greater omentum. A dose of 2 × 10 MSCs was injected into the space between the greater omentum and the left kidney. Equal amounts of MSCs were administered under ultrasound guidance every second week for a total of 4 treatments. Mice were sacrificed 4 weeks after surgery. Serum creatinine and blood urea levels were measured to assess renal function. qPCR, Western blot, and histological analyses were conducted to further investigate the therapeutic mechanism of MSCs.

Results: Ultrasound-guided injection of MSCs into the greater omentum that surrounds the kidney enriched cells in the kidney region for up to 5 days. Renal function tests indicated that MSCs improved renal function to a great extent, as reflected by decreased blood urea nitrogen and serum creatinine levels. In addition, histological analyses showed that MSCs noticeably attenuated kidney injury, as evidenced by the amelioration of tubular necrosis and peritubular interstitial fibrosis. Mitigation of renal interstitial fibrosis was further confirmed by immunohistochemistry, qPCR, and western blotting after MSC treatment. Moreover, immunofluorescence staining revealed that MSCs alleviated inflammatory responses by increasing the counts of CD206+ cells and decreasing the counts of CD68+ cells. MSC migration was initiated in response to AA-I-treated renal epithelial cells in an in vitro migration assay.

Conclusions: These findings suggested that administration of MSCs into the cavity formed by the injured kidney and the greater omentum under ultrasound guidance improved renal function, attenuated kidney injury, and mitigated renal interstitial fibrosis and inflammatory responses. Thus, this approach might be a safe and effective therapy for CKD.
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http://dx.doi.org/10.1186/s13287-021-02243-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8091698PMC
May 2021

Establishment of PLAFMCi004-A induced pluripotent stem cells derived from PBMCs from a healthy individual.

Stem Cell Res 2021 05 5;53:102316. Epub 2021 Apr 5.

Department of Nephrology, The First Medical Center, Chinese PLA General Hospital, Medical School of Chinese PLA, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing 100853, China. Electronic address:

Peripheral blood mononuclear cells (PBMCs) were isolated from a healthy male individual. PBMCs were reprogrammed into human induced pluripotent stem cells (iPSCs) using plasmids carrying the following reprogramming factors: NANOG, LIN28, OCT4, SOX2, c-MYC, and KLF4. This cell line expressed pluripotency markers, exhibited the normal male karyotype (46, XY), and had the potential to differentiate into 3 germ layers, as confirmed by techniques such as flow cytometry. The iPSC obtained from a healthy individual can be used for organoids to reveal developmental mechanism of tissue and organ regeneration, stem cell therapy and drug screening.
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http://dx.doi.org/10.1016/j.scr.2021.102316DOI Listing
May 2021

Grb2 Induces Cardiorenal Syndrome Type 3: Roles of IL-6, Cardiomyocyte Bioenergetics, and Akt/mTOR Pathway.

Front Cell Dev Biol 2021 22;9:630412. Epub 2021 Mar 22.

Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases, Beijing, China.

Cardiorenal syndrome type 3 (CRS-3) is damage to the heart following acute kidney injury (AKI). Although many experiments have found that inflammation, oxidative stress, and cardiomyocyte death are involved in cardiomyocyte pathophysiological alterations during CRS-3, they lack a non-bias analysis to figure out the primary mediator of cardiac dysfunction. Herein proteomic analysis was operated in CRS-3 and growth factor receptor-bound protein 2 (Grb2) was identified as a regulator involving AKI-related myocardial damage. Increased Grb2 was associated with cardiac diastolic dysfunction and mitochondrial bioenergetics impairment; these pathological changes could be reversed through the administration of a Grb2-specific inhibitor during AKI. Molecular investigation illustrated that augmented Grb2 promoted cardiomyocyte mitochondrial metabolism disorder through inhibiting the Akt/mTOR signaling pathway. Besides that, Mouse Inflammation Array Q1 further identified IL-6 as the upstream stimulator of Grb2 upregulation after AKI. Exogenous administration of IL-6 induced cardiomyocyte damage and mitochondrial bioenergetics impairment, whereas these effects were nullified in cardiomyocytes pretreated with Grb2 inhibitor. Our results altogether identify CRS-3 to be caused by the upregulations of IL-6/Grb2 which contribute to cardiac dysfunction through inhibiting the Akt/mTOR signaling pathway and inducing cardiomyocyte mitochondrial bioenergetics impairment. This finding provides a potential target for the clinical treatment of patients with CRS-3.
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http://dx.doi.org/10.3389/fcell.2021.630412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019825PMC
March 2021

Interpretable Machine Learning Model for Early Prediction of Mortality in ICU Patients with Rhabdomyolysis.

Med Sci Sports Exerc 2021 Sep;53(9):1826-1834

Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, CHINA.

Purpose: Rhabdomyolysis (RM) is a complex set of clinical syndromes that involves the rapid dissolution of skeletal muscles. Mortality from RM is approximately 10%. This study aimed to develop an interpretable and generalizable model for early mortality prediction in RM patients.

Method: Retrospective analyses were performed on two electronic medical record databases: the eICU Collaborative Research Database and the Medical Information Mart for Intensive Care III database. We extracted data from the first 24 h after patient ICU admission. Data from the two data sets were merged for further analysis. The merged data sets were randomly divided, with 70% used for training and 30% for validation. We used the machine learning model extreme gradient boosting (XGBoost) with the Shapley additive explanation method to conduct early and interpretable predictions of patient mortality. Five typical evaluation indexes were adopted to develop a generalizable model.

Results: In total, 938 patients with RM were eligible for this analysis. The area under the receiver operating characteristic curve (AUC) of the XGBoost model in predicting hospital mortality was 0.871, the sensitivity was 0.885, the specificity was 0.816, the accuracy was 0.915, and the F1 score was 0.624. The XGBoost model performance was superior to that of other models (logistic regression, AUC = 0.862; support vector machine, AUC = 0.843; random forest, AUC = 0.825; and naive Bayesian, AUC = 0.805) and clinical scores (Sequential Organ Failure Assessment, AUC = 0.747; Acute Physiology Score III, AUC = 0.721).

Conclusions: Although the XGBoost model is still not great from an absolute performance perspective, it provides better predictive performance than other models for estimating the mortality of patients with RM based on patient characteristics in the first 24 h of admission to the ICU.
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http://dx.doi.org/10.1249/MSS.0000000000002674DOI Listing
September 2021

Outcomes and risk management in type B aortic dissection patients with acute kidney injury: a concise review.

Ren Fail 2021 Dec;43(1):585-596

The Nephrology Department, Xijing Hospital, The Fourth Military Medical University, Xi'an, PR China.

Purpose: Type B aortic dissection is a rare but life-threatening disease. Thoracic endovascular aortic repair (TEVAR) was widely used for Type B aortic dissection patients in the last decade due to the lower mortality and morbidity compared with open chest surgical repair (OCSR). AKI in type B aortic dissection is a well-recognized complication and indicates poor short-term and long-term outcome. The objective of this concise review was to identify the risk factors and the impact of AKI on type B aortic dissection patients.

Methods And Results: A literature search was performed using PubMed, Embase, MEDLINE, and Cochrane Library with the search terms 'type B aortic dissection' and 'acute kidney injury' (AKI), and all English-language literatures published in print or available online from inception through August 2020 were thoroughly reviewed. Studies that reported relative AKI risks and outcomes in type B aortic dissection patient were included. Major mechanisms of AKI in type B aortic dissection included renal hypoperfusion, inflammation response, and the use of contrast medium. Type B aortic dissection patients with AKI significantly had increased hospital stay duration, need of renal replacement therapy, and 30-d and 1-year mortality.

Conclusions: AKI in type B aortic dissection is a well-recognized complication and associated with poor short-term and long-term outcome. Early identification of high-risk patients, early diagnosis of AKI, stabilization of the hemodynamic parameters, avoidance of nephrotoxic drugs, and optimization of the use of contrast agents are the major strategies for the reduction of AKI in type B aortic dissection patients.
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http://dx.doi.org/10.1080/0886022X.2021.1905664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018386PMC
December 2021

Lowest nocturnal systolic blood pressure is related to heavy proteinuria and outcomes in elderly patients with chronic kidney disease.

Sci Rep 2021 Mar 12;11(1):5846. Epub 2021 Mar 12.

Department of Nephrology, The First Medical Centre, Chinese PLA General Hospital, 28 Fuxing Road, Haidian District, Beijing, China.

Ambulatory blood pressure monitoring (ABPM) can produce many variables, of which the lowest nocturnal systolic blood pressure (LNSBP) currently used in calculating morning surge is occasionally overlooked in recent kidney studies compared with other ABPM parameters. We explored the clinical effects of LNSBP in elderly patients with chronic kidney disease (CKD) in a multicenter, observational cohort study. A total of 356 elderly patients with CKD from 19 clinics were included in this analysis. We used multiple logistic regression and survival analyses to assess the associations between the lowest nocturnal systolic blood pressure and heavy proteinuria and kidney disease outcomes, respectively. The median age was 66 years, and 66.6% were men. The median eGFR was 49.2 ml/min/1.73 m. Multivariate logistic regression analysis demonstrated that LNSBP (OR 1.24; 95% CI 1.10-1.39; P < 0.001; per 10 mmHg) was associated with heavy proteinuria. During the median follow-up of 23 months, 70 patients (19.7%) had a composite outcome; of these, 25 initiated dialysis, 25 had 40% eGFR loss, and 20 died. Cox analysis showed that the renal risk of LNSBP for CKD outcomes remained significant even after adjusting for background factors, including age, sex, medical history of hypertension and diabetes, smoking status, eGFR, 24-h proteinuria, and etiology of CKD (HR 1.18; 95% CI 1.06-1.32; P = 0.002; per 10 mmHg). Concentrating on LNSBP could be valuable in guiding antihypertensive treatment to control heavy proteinuria and improve renal prognosis in elderly CKD patients.
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http://dx.doi.org/10.1038/s41598-021-85071-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955052PMC
March 2021

Regulation of connective tissue growth factor expression by miR-133b for the treatment of renal interstitial fibrosis in aged mice with unilateral ureteral obstruction.

Stem Cell Res Ther 2021 03 10;12(1):171. Epub 2021 Mar 10.

Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, 28 Fuxing Road, Beijing, China.

Introduction: Renal interstitial fibrosis, an important pathological feature of kidney aging and chronic renal failure, is regulated by mesenchymal stem cells (MSCs). We have previously demonstrated low expression of miR-133b in MSC-derived extracellular vesicles (MSC-EVs) in aged rats. However, miR-133b can mediate the inhibition of epithelial-mesenchymal transition (EMT) of renal tubules induced by transforming growth factor-β1 (TGF-β1). We investigated the effect of miR-133b for the treatment of geriatric renal interstitial fibrosis and evaluated its target genes.

Methods: We performed real-time polymerase chain reaction to detect miR-133b expression induced during EMT of HK2 cells by TGF-β1 at different concentrations (0, 6, 8, and 10 ng/mL) and at different time points (0, 24, 48, and 72 h). The target genes of miR-133b were validated using the dual-luciferase reporter assay. In vitro experiments were performed to evaluate mRNA and protein expression of miR-133b targets, E-cadherin, α-smooth muscle actin (SMA), fibronectin, and collagen 3A1 (Col3A1), in HK2 cells transfected with miR-133b under TGF-β1 stimulation. A 24-month-old unilateral ureteral obstruction (UUO) mouse model was established and injected with transfection reagent and miR-133b into the caudal vein. The target gene of miR-133b and other parameters mentioned above such as mRNA and protein expression levels and renal interstitial fibrosis were detected at 7 and 14 days.

Results: miR-133b expression gradually decreased with an increase in TGF-β1 concentration and treatment time, and the miR-133b mimic downregulated connective tissue growth factor (CTGF) expression. The dual-luciferase reporter assay confirmed CTGF as a direct target of miR-133b. Transfection of the miR-133b mimic inhibited TGF-β1-induced EMT of HK2 cells; this effect was reversed by CTGF overexpression. miRNA-133b expression significantly increased (approximately 70-100 times) in mouse kidney tissues after injection of the miRNA-133b overexpression complex, which significantly alleviated renal interstitial fibrosis in mice with UUO.

Conclusion: miR-133b exerted targeted inhibitory effects on CTGF expression, which consequently reduced TGF-β1-induced EMT of HK2 cells and renal interstitial fibrosis in aged mice with UUO.
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http://dx.doi.org/10.1186/s13287-021-02210-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944614PMC
March 2021

Bilirubin adsorption for the treatment of severe hyperbilirubinemia after cardiac surgery: A retrospective cohort study.

Int J Artif Organs 2021 Mar 8:391398821997841. Epub 2021 Mar 8.

The Nephrology Department of Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, China.

Objective: Severe hyperbilirubinemia after cardiac surgery increases in-hospital and 1-year mortality. Our present study aimed to analyze the safety and efficacy of bilirubin adsorption (BA) in patients with post-cardiac-surgery severe hyperbilirubinemia.

Methods: We retrospectively included patients who underwent BA due to severe hyperbilirubinemia after cardiac surgery in our center between January 2015 and December 2018. The change of serum bilirubin, alanine aminotransferase, aspartate aminotransferase, and 30-day and 1-year mortality were assessed as endpoints. Univariate and multivariate analyses were employed to identify the risk factors of patient 30-day mortality.

Result: A total of 25 patients with 44 BA treatments were included. One BA treatment reduced total bilirubin (TB) concentration from 431.65 ± 136.34 to 324.83 ± 129.44 µmol/L ( < 0.001), with a reduction rate of 24.8%. No clinically relevant thrombosis of the extracorporeal circuit occurred during the BA treatment. The 30-day and 1-year mortality rates were 68% ( = 18) and 84% ( = 21), respectively. Multivariate analysis identified that TB level before BA treatment (odds ratio [OR] 1.010, 95% confidence interval [CI] 1.000-1.019;  = 0.043) was an independent risk factor of 30-day mortality.

Conclusions: BA treatment should be considered as an effective and safe method for the reduction of serum bilirubin in patients with post-cardiac-surgery severe hyperbilirubinemia. Patients with higher TB level before BA treatment had a relatively increased risk of 30-day mortality. Further studies are needed to evaluate the timing of BA for severe hyperbilirubinemia after cardiac surgery.
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http://dx.doi.org/10.1177/0391398821997841DOI Listing
March 2021

Mesangial C3 deposition and serum C3 levels predict renal outcome in IgA nephropathy.

Clin Exp Nephrol 2021 Jun 23;25(6):641-651. Epub 2021 Feb 23.

Department of Nephrology, Beijing Children's Hospital, Capital Medical University, Beijing, 100045, China.

Background: Complement activation plays an important role in the pathogenesis of IgA nephropathy (IgAN). We aimed to evaluate the relationship between mesangial C3 deposition and histologic lesions and to investigate the role of mesangial C3 deposition and serum C3 reduction in predicting renal outcome in IgAN children.

Methods: We performed a retrospective cohort study in children with biopsy-proven IgAN. Mesangial C3 deposition (< 2+ vs. ≥ 2+) was detected by the immunofluorescence. Histopathologic kidney grades were determined by the Oxford classification. A decreased serum C3 concentration (hypoC3) was defined when C3 < 90 mg/dl. The endpoint was composite kidney outcome with either a 30% decline in glomerular filtration rates from baseline or kidney failure during the follow-up period.

Results: A total of 98 children were analyzed. Mesangial hypercellularity (M) was an independent factor associated with mesangial C3 deposition (HR 3.267; 95% CI 1.028-10.389; P = 0.045). After a median follow-up period of 25 months (interquartile range 18-36 months), 6 (6.1%) children reached the endpoint. Compared with other children, a significantly higher proportion of children with composite kidney outcomes had mesangial C3 deposition ≥ 2+ and hypoC3 (3.4% versus 27.3%, P = 0.002). After adjustment for clinicopathologic risk factors, mesangial C3 deposition ≥ 2+ and hypoC3 were associated with renal outcome (HR 9.772; 95% CI 1.264-75.518; P = 0.029).

Conclusion: Mesangial C3 deposition was associated with M in IgAN. Mesangial C3 deposition and hypoC3 were risk factors for renal outcome in children with IgAN.
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http://dx.doi.org/10.1007/s10157-021-02034-7DOI Listing
June 2021

Evaluating the safety and efficacy of argatroban locking solution in the prevention of the dysfunction of haemodialysis central venous catheters: a study protocol for a randomized controlled trial.

Ann Palliat Med 2021 Feb 25;10(2):2260-2270. Epub 2021 Jan 25.

Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, China.

Background: Use of anticoagulant as lock solutions is an important method to maintain the function of haemodialysis (HD) central venous catheters (CVCs), and the common anticoagulants heparin and citrate are not suitable for some patients. Argatroban can inhibit thrombin directly, has a definite anticoagulant effect, and is expected to be a new anticoagulant for CVC lock solutions.

Methods: A total of 60 HD patients with non-tunnelled or tunnelled CVCs will be randomly assigned to two groups: an argatroban group and a control group. The participants will be given argatroban 0.5 mg/mL or unfractionated heparin (UFH) 1,000 U/mL locked post-dialysis instilled into the CVC lumens and followed up for 2 weeks. Data on demographic and general clinical information, laboratory examination, adverse events, adverse reactions and serious adverse events in the two groups will be collected. The differences in coagulation indexes at 30 min following catheter lock will be compared. The thrombosis rate, infection rate and percentage of catheter-days in the two groups will be observed. The primary outcomes include: efficacy assessments of combined outcome events: (I) rates of cumulative catheter survival in the 2-week HD session (the standard of catheter survival was catheter mean blood flow ≥250 mL/min); (II) rates of cumulative survival free of catheter thrombosis in the 2-week HD session. The second outcomes include: catheter dysfunction, the variation value (seconds) in activated partial thromboplastin time (aPTT) at 30 min following catheter locking and aPTT before next dialysis, catheter-associated bleeding, and catheterassociated infections.

Discussion: At present, there is no clinical study of argatroban as a CVC lock solution. This study will explore the efficacy and safety of the argatroban as locking solution in the prevention of the dysfunction of HD CVCs to provide evidence for further research.

Trial Registration: Chinese Clinical Trial Registry, ChiCTR1800017105. Registered 12 July, 2018 (prospectively registered, http://www.chictr.org.cn/showproj.aspx?proj=29054).
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http://dx.doi.org/10.21037/apm-20-1641DOI Listing
February 2021

Deoxycholic Acid Upregulates Serum Golgi Protein 73 through Activating NF-κB Pathway and Destroying Golgi Structure in Liver Disease.

Biomolecules 2021 02 2;11(2). Epub 2021 Feb 2.

Department of Microbiology and Infectious Disease Center, School of Basic Medical Science, Peking University Health Science Center, Beijing 100191, China.

Golgi protein 73 (GP73) is upregulated in a variety of liver diseases, yet the detailed mechanism is poorly characterized. We analyzed GP73 in a retrospective cohort including 4211 patients with chronic liver disease (CLD) or hepatocellular carcinoma (HCC). The effect of deoxycholic acid (DCA) and nuclear factor-kappa B (NF-κB) on expression and release of GP73 in Huh-7 and SMMC7721 cells were studied. A mouse study was used to confirm our findings in vivo. A positive correlation was found between serum GP73 and total bile acid (TBA) in cirrhotic patients ( = 0.540, < 0.001), higher than that in non-cirrhotic CLD ( = 0.318, < 0.001) and HCC ( = 0.353, < 0.001) patients. In Huh-7 and SMMC7721 cells, DCA upregulated the expression and release of GP73 in a dose- and time-dependent manner. After overexpressing NF-κB p65, the promoter activity, GP73 messenger RNA (mRNA) level, and supernatant GP73 level were increased. The promotion effect of DCA on GP73 release was attenuated after inhibiting the NF-κB pathway. Mutating the binding sites of NF-κB in the sequence of the GP73 promoter led to a declined promoting effect of DCA on GP73. The upregulation role of DCA in GP73 expression through the NF-κB pathway was confirmed in vivo. In addition, exposure to DCA caused disassembly of Golgi apparatus. In summary, DCA upregulates the expression and release of GP73 via activating the NF-κB pathway and destroying the Golgi structure.
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http://dx.doi.org/10.3390/biom11020205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913056PMC
February 2021
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