Long-term kidney transplant outcomes in Chinese patients with primary glomerulonephritis:A multicenter study in China

To the Editor:The primary cause of end-stage kidney disease(ESKD)in China is chronic glomerulonephritis(GN),which accounts for 45%of ESKD patients.[1]There is currently no nationwide large-scale study on the longterm prognosis of kidney transplantation in patients with chronic GN in China.Over the past decade,however,few landmark studies from populations in Europe[2,3]and the United States[4]have provided important reference data for this issue.Therefore,we propose to conduct a nationwide multicenter retrospective study,which was launched by the National Clinical Research Center of Kidney Diseases,Jinling Hospital,Nanjing University School of Medicine,from 2017 to 2020.

Mitochondrial Regulation of Macrophages in Innate Immunity and Diverse Roles of Macrophages During Cochlear Inflammation

Macrophages are essential components of the innate immune system and constitute a non-specific first line of host defense against pathogens and inflammation.Mitochondria regulate macrophage activation and innate immune responses in various inflammatory diseases,including cochlear inflammation.The distribution,number,and morphological characteristics of cochlear macrophages change significantly across different inner ear regions under various pathological conditions,including noise exposure,ototoxicity,and age-related degeneration.However,the exact mechanism underlying the role of mitochondria in macrophages in auditory function remains unclear.Here,we summarize the major factors and mitochondrial signaling pathways(e.g.,metabolism,mitochondrial reactive oxygen species,mitochondrial DNA,and the inflammasome)that influence macrophage activation in the innate immune response.In particular,we focus on the properties of cochlear macrophages,activated signaling pathways,and the secretion of inflammatory cytokines after acoustic injury.We hope this review will provide new perspectives and a basis for future research on cochlear inflammation.

Netrin-1 works with UNC5B to regulate angiogenesis in diabetic kidney disease

Netrin-1,an axon guidance factor,and its receptor UNC5B play important roles in axonal development and angiogenesis.This study examined netrin-1 and UNC5B expression in kidneys with diabetic kidney disease (DKD) and investigated their roles in angiogenesis.Netrin-1 and UNC5B were upregulated in streptozotocininduced DKD Wistar rats,and their expression was compared with that in healthy controls.However,exogenous netrin-1 in UNC5B-depleted human renal glomerular endothelial cells (HRGECs) inhibited cell migration and tubulogenesis.This effect was likely associated with SRC pathway deactivation.Netrin-1 treatment also eliminated the pro-angiogenic effects of exogenous VEGF-165 on UNC5B-silenced HRGECs.These results indicate that UNC5B antagonizes netrin-1 and that UNC5B upregulation contributes partly to enhancing angiogenesis in DKD.Therefore,introducing exogenous netrin-1 and depleting endogenous UNC5B are potential strategies for reducing the incidence of early angiogenesis and mitigating kidney injury in DKD.

YWHAZ Binds to TRIM21 but Is Not Involved in TRIM21-stimulated Osteosarcoma Cell Proliferation

Objective Osteosarcoma is the most common type of malignant bone tumor in children and adolescents. The role of E3 ligases in tumorigenesis is currently a focus in tumor research. In the present study, we investigated the role of the E3 ligase tripartite motif 21（TRIM21） in osteosarcoma cell proliferation.Methods 3-（4, 5-dimethylthiazol-2-yl）-2, 5-diphenyltetrazolium bromide（MTT） assays were used to assess osteosarcoma cell viability. U2-OS cells stably carrying a recombinant lentivirus expressing tetracycline-regulated TRIM21 were screened. Co-immunoprecipitation was coupled with LCMS/MS analysis to identify novel interacting partners of TRIM21. Co-immunoprecipitation and bimolecular fluorescence complementation（BIFC） were performed to validate the interactions between TRIM21 and its novel partner YWHAZ. A TRIM21-ΔRING construct was generated to test the effects of TRIM21 ligase activity on YWHAZ.Results TRIM21 positively regulated osteosarcoma cell proliferation. Overexpression of TRIM21 enhanced osteosarcoma cell tolerance toward various stresses. YWHAZ protein was identified as a novel interacting partner of TRIM21 and its expression levels were negatively regulated by TRIM21. The RING domain of TRIM21 was required for TRIM21 negative regulation of YWHAZ expression. However,overexpression of YWHAZ did not affect positive regulation of osteosarcoma cell proliferation by TRIM21.Conclusion Our results further clarify the molecular mechanisms underlying the pathogenesis of osteosarcoma.

2018世界肾脏日：关注女性和肾脏疾病

女性是现代家庭和社会的重要贡献者。但目前在世界范围内,男性和女性在受教育程度、医疗保健等方面仍存在显著差异。2018年第13个世界肾脏日恰逢国际妇女节,其主题是"肾脏和女性健康",给我们提供了一个关注女性健康,尤其是女性肾脏健康的重要契机。为此,世界肾脏日指导委员会(World Kidney Day Steering Committee)特别组织了全球具有代表性的5位女性肾脏病学家,撰写了述评文章,借机呼吁肾脏病学术领域和全社会更加重视女性健康,让更多女性从肾脏病学术研究中获益。关注女性肾脏健康,利在当代功在千秋!

A kidney-brain neural circuit drives progressive kidney damage and heart failure

Chronic kidney disease(CKD)and heart failure(HF)are highly prevalent,aggravate each other,and account for substantial mortality.However,the mechanisms underlying cardiorenal interaction and the role of kidney afferent nerves and their precise central pathway remain limited.Here,we combined virus tracing techniques with optogenetic techniques to map a polysynaptic central pathway linking kidney afferent nerves to subfornical organ(SFO)and thereby to paraventricular nucleus(PVN)and rostral ventrolateral medulla that modulates sympathetic outflow.This kidney-brain neural circuit was overactivated in mouse models of CKD or HF and subsequently enhanced the sympathetic discharge to both the kidney and the heart in each model.Interruption of the pathway by kidney deafferentation,selective deletion of angiotensin II type 1a receptor(AT1a)in SFO,or optogenetic silence of the kidney-SFO or SFO-PVN projection decreased the sympathetic discharge and lessened structural damage and dysfunction of both kidney and heart in models of CKD and HF.Thus,kidney afferent nerves activate a kidney-brain neural circuit in CKD and HF that drives the sympathetic nervous system to accelerate disease progression in both organs.These results demonstrate the crucial role of kidney afferent nerves and their central connections in engaging cardiorenal interactions under both physiological and disease conditions.This suggests novel therapies for CKD or HF targeting this kidney-brain neural circuit.

A novel machine learning-assisted clinical diagnosis support model for early identification of pancreatic injuries in patients with blunt abdominal trauma:a cross-national study

Background:The recognition of pancreatic injury in blunt abdominal trauma is often severely delayed in clinical practice.The aim of this study was to develop a machine learning model to support clinical diagnosis for early detection of abdominal trauma.Methods:We retrospectively analyzed of a large intensive care unit database(Medical Information Mart for Intensive Care[MIMIC]-IV)for model development and internal validation of the model,and performed outer validation based on a cross-national data set.Logistic regres-sion was used to develop three models(PI-12,PI-12-2,and PI-24).Univariate and multivariate analyses were used to determine variables in each model.The primary outcome was early detection of a pancreatic injury of any grade in patients with blunt abdominal trauma in the first 24 hours after hospitalization.Results:The incidence of pancreatic injuries was 5.56%(n=18)and 6.06%(n=6)in the development(n=324)and internal validation(n=99)cohorts,respectively.Internal validation cohort showed good discrimination with an area under the receiver operator characteristic curve(AUC)value of 0.84(95%confidence interval[CI]:0.71–0.96)for PI-24.PI-24 had the best AUC,specificity,and positive predictive value(PPV)of all models,and thus it was chosen as the final model to support clinical diagnosis.PI-24 performed well in the outer validation cohort with an AUC value of 0.82(95%CI:0.65–0.98),specificity of 0.97(95%CI:0.91–1.00),and PPV of 0.67(95%CI:0.00–1.00).Conclusion:A novel machine learning-based model was developed to support clinical diagnosis to detect pancreatic injuries in patients with blunt abdominal trauma at an early stage.

Biomarkers of aging

Aging biomarkers are a combination of biological parameters to(i)assess age-related changes,(ii)track the physiological aging process,and(iii)predict the transition into a pathological status.Although a broad spectrum of aging biomarkers has been developed,their potential uses and limitations remain poorly characterized.An immediate goal of biomarkers is to help us answer the following three fundamental questions in aging research:How old are we?Why do we get old?And how can we age slower?This review aims to address this need.Here,we summarize our current knowledge of biomarkers developed for cellular,organ,and organismal levels of aging,comprising six pillars:physiological characteristics,medical imaging,histological features,cellular alterations,molecular changes,and secretory factors.To fulfill all these requisites,we propose that aging biomarkers should qualify for being specific,systemic,and clinically relevant.

Sonic hedgehog signaling in kidney fibrosis: a master communicator

The hedgehog signaling cascade is an evolutionarily conserved pathway that regulates multiple aspects of embryonic development and plays a decisive role in tissue homeostasis. As the best studied member of three hedgehog ligands, sonic hedgehog(Shh) is known to be associated with kidney development and tissue repair after various insults. Recent studies uncover an intrinsic link between dysregulated Shh signaling and renal fibrogenesis. In various types of chronic kidney disease(CKD), Shh is upregulated specifically in renal tubular epithelium but targets interstitial fibroblasts, thereby mediating a dynamic epithelialmesenchymal communication(EMC). Tubule-derived Shh acts as a growth factor for interstitial fibroblasts and controls a hierarchy of fibrosis-related genes, which lead to the excessive deposition of extracellular matrix in renal interstitium. In this review, we recapitulate the principle of Shh signaling, its activation and regulation in a variety of kidney diseases. We also discuss the potential mechanisms by which Shh promotes renal fibrosis and assess the efficacy of blocking this signaling in preclinical settings. Continuing these lines of investigations will provide novel opportunities for designing effective therapies to improve CKD prognosis in patients.

Potential association of hyperhomocysteinemia with the progression of IgA nephropathy： a retrospective study

Background The high blood homocysteine （Hcy） levels found in patients with hyperhomocysteinemia （HHcy） have been implicated in an increased risk of cardiovascular disease morbidity and mortality in end-stage renal disease （ESRD）.This study investigated the association of HHcy with progression of IgA nephropathy.Methods We analyzed 108 participants newly diagnosed with IgA nephropathy between August 2005 and August 2007 in the Department of Nephrology,Chinese People＇s Liberation Army General Hospital.The association between clinicopathological factors and the Hcy levels were analyzed by Logistic regression and those with ESRD risk were analyzed by Cox regression.Results Patients were aged （35.71±10.73） years and included 45.71％ women and 12.04％ patients with HHcy.In multivariate Logistic regression analysis,HHcy was associated with arterial lesions （OR 2.60; 95％ CI 1.55-4.34; P＜0.001） even when age,body mass index,estimated glomerular filtration rate,mean arterial pressure,and initial proteinuria were taken into account.Mean follow-up was （67.37±16.21） months.HHcy was also associated with worse ESRD-free survival （HR 4.71; 95％ CI 1.45 to 15.31; P=0.010）.Conclusion HHcy is associated with the risk of intrarenal arterial lesions and may be useful for estimating the prognosis of IgA nephropathy.

Secreted miR-34a in astrocytic shedding vesicles enhanced the vulnerability of dopaminergic neurons to neurotoxins by targeting Bcl-2

MicroRNAs （miRNAs） are a class of noncoding RNAs that regulates target gene expression at posttranscrip- tional level, leading to further biological functions. We have demonstrated that microvesicles （MVs） can deliver miRNAs into target cells as a novel way of intercellular communication. It is reported that in central nervous system, glial cells release MVs, which modulate neu-ronal function in normal condition. To elucidate the potential role of glial MVs in disease, we evaluated the effects of secreted astrocytic MVs on stress condition. Our results demonstrated that after Lipopolysaccharide （LPS） stimulation, astrocytes released shedding vesi- cles （SVs） that enhanced vulnerability of dopaminergic neurons to neurotoxin. Further investigation showed that increased astrocytic miR-34a in SVs was involved in this progress via targeting anti-apoptotic protein Bcl-2 in dopaminergic neurons. We also found that inhibition of astrocytic miR-34a after LPS stimulation can postpone dopaminergic neuron loss under neurotoxin stress. These data revealed a novel mechanism underlying astrocyte-neuron interaction in disease.

Critical hubs of renal ischemia-reperfusion injury:endoplasmic reticulum-mitochondria tethering complexes

Mitochondrial injury and endoplasmic reticulum(ER)stress are considered to be the key mechanisms of renal ischemia-reperfusion(I/R)injury.Mitochondria are membrane-bound organelles that form close physical contact with a specific domain of the ER,known as mitochondrial-associated membranes.The close physical contact between them is mainly restrained by ER-mitochondria tethering complexes,which can play an important role in mitochondrial damage,ER stress,lipid homeostasis,and cell death.Several ER-mitochondria tethering complex components are involved in the process of renal I/R injury.A better understanding of the physical and functional interaction between ER and mitochondria is helpful to further clarify the mechanism of renal I/R injury and provide potential therapeutic targets.In this review,we aim to describe the structure of the tethering complex and elucidate its pivotal role in renal I/R injury by summarizing its role in many important mechanisms,such as mitophagy,mitochondrial fission,mitochondrial fusion,apoptosis and necrosis,ER stress,mitochondrial substance transport,and lipid metabolism.

Association of Estrogen Receptor Gene Polymorphisms and Primary Biliary Cirrhosis in a Chinese Population： A Case- Control Study

Background： Primary biliary cirrhosis （PBC） is a chronic and slowly progressive cholestatic liver disease characterized by destruction of the interlobular bile ducts and a striking female predominance, The aim of this study was to identity associations between estrogen receptor （ESR） gene polymorphisms with the risk of developing PBC and abnormal serum liver tests in a Chinese population. Methods： Thirty-six patients with PBC （case group） and 35 healthy individuals （control group） from the First Hospital of Jilin University were studied. Whole genomic DNA was extracted from all the participants. Three single-nucleotide polymorphisms （rs2234693~ rs2228480, and rs3798577） from ESR1 and two （rs1256030 and rs1048315） from ESR2 were analyzed by a pyrosequencing method. Demographic data and liver biochemical data were collected. Results： Subjects with the T allele at ESR2 rs1256030 had 1.5 times higher risk of developing PBC than those with the C allele （odds ratio [OR] = 2.1277, 95% confidence interval [CI] = 1.1872-4.5517）. Haplotypes TGC of ESRI rs2234693, rs2228480, and rs3798577 were risk thctors for having PBC. The C allele at ESRI rs2234693 was associated with abnormal alkaline phosphatase （OR 5.2469, 95% CI = 1.3704-20.0895） and gamma-glutamyl transferase （OR = 3.4286, 95% CI = 1.0083-13.6578） levels in PBC patients. Conclusions： ESR2 rs1256030 T allele may be a significant risk factor for the development of PBC. Screening for patients with gene polymorphisms may help to make early diagnoses in patients with PBC.

Fibronectin Glomerulopathy： A Rare Autosomal Dominant Glomerular Disease

A 43-year-old female was admitted to the Department of Nephrology at Jinling Hospital （Nanjing,China） in January 2017 complaining of edema for 3 months with urine abnormalities.Her father had renal disease （with no biopsy performed） when he was 40 years old and died of uremia at 56 years old.Her mother and brother were healthy;however,her daughter and nephew （her brother＇s son） had slightly high microalbumin levels in routine urine screenings.Her daughter＇s urinary protein level was weakly positive,whereas her nephew＇s urinary protein level was negative.

Comparative analysis of membranous and other nephropathy subtypes and establishment of a diagnostic model

This study aimed to compare clinical features between membranous nephropathy (MN) and nonmembranous nephropathy (non-MN), to explore the clinically difTerential diagnosis of these two types, and to establish a diagnostic model of MN. After renal biopsy was obtained, 798 patients were divided into two groups based on their examination results: primary MN group (n = 248) and non-MN group (n = 550). Their data were statistically analyzed. Logistic regression analysis indicated that anti-PLA2R antibodies, IgG, and Cr were independently correlated with MN, and these three parameters were then used to establish the MN diagnostic model. A receiver operating characteristic (ROC) curve confirmed that our diagnostic model could distinguish between patients with and without MN, and their corresponding sensitivity, specificity, and AUC were 79.9%, 89.4%, and 0.917, respectively. The cutoff value for this combination in MN diagnosis was 0.34. The established diagnostic model that combined multiple factors shows a potential for broad clinical applications in differentiating primary MN from other kidney diseases and provides reliable evidence supporting the feasibility of noninvasive diagnosis of kidney diseases.

Current status of anticoagulant treatments and improvements for hemodialysis patients in northern Chinese cities： a five-year comparative study

Background Anticoagulation treatments are an important aspect of hemodialysis; however,few reports have addressed these treatments.This investigation intends to increase the understanding of the current status and improvements of hemodialysis-related anticoagulation treatments in China.Methods In this study,an epidemiological investigation was conducted that examined 842 patients in 2007 and 1 175patients in 2012 who underwent hemodialysis anticoagulation treatments in seven blood purification centers in northern Chinese cities.Results Heparin was the most commonly used anticoagulant,although the percentage of use of low-molecular-weight heparin （LMWH） increased from 26.5% in 2007 to 42.1% in 2012.In 2007,there were no significant differences in anticoagulant selection among either patients with various primary diseases or patients with hemorrhage,thrombosis,thrombocytopenia,or a low hemoglobin level.However,compared with patients with other diseases,significantly lower doses of LMWH were administered to patients with hypertension （55.5 U/kg vs.67.3 U/kg,P 〈0.05） or diabetes （58.5 U/kg vs.67.3 U/kg,P 〈0.05）,and patients with hemorrhage received lower doses of heparin than the other patients （61.6 U/kg vs.71.8 U/kg,P 〈0.01）.In 2012,patients with diabetic nephropathy （51.5% vs.36.5%,P 〈0.01）,hemorrhage （43.4% vs.31.7%,P 〈0.01）,or a hemoglobin level below 90 g/L （57.2% vs.37.1%,P 〈0.01） experienced significantly higher doses of LMWH administration; patients with hemorrhage received significantly reduced LMWH dosages （50.4 U/kg vs.57.8 U/kg,P 〈0.05）,and patients with thrombosis received significantly higher doses of heparin （73.8 U/kg vs.62.1 U/kg,P 〈0.01） or LMWH （57.8 U/kg vs.52.6 U/kg,P 〈0.05）.Antiplatelet drugs were administered to 20.4% of the examined patients in 2007 and 20.7% in 2012.In 2012,patients with hypertension （25.9% vs.18.5%,P 〈0.01） and thrombosis （36.6% vs.16.1%,P 〈0.01） had a higher rate of using antiplatelet drugs than patients with other primary diseases and complications.Patients receiving antiplatelet drugs also received higher doses of heparin than patients without using antiplatelet drugs （74.4 U/kg vs.65.9 U/kg,P 〈0.01）.However,the use of the drugs was not correlated with thrombocytopenia.The rate at which coagulation indices were determined increased from 45.7% in 2007 to 64% in 2012.Conclusion These findings suggested that hemodialysisrelated anticoagulation treatments in China have gradually become more standardized and individualized.

Identification of Transcription Regulatory Relationships in Diabetic Nephropathy

To the Editor:Diabetic nephropathy (DN)is the leading cause of chronic renal diseases and accounts for almost 50% of all end-stage renal diseases worldwide.The prevalence of DN increased significantly after 2010in China.[1,2] DN is clinically characterized by proteinuria and morphological and ultrastructural changes in the kidney.The pathogenesis of DN is multifactorial and extremely complex,including hyperglycemia,transforming growth factor (TGF)-β1,angiotensin Ⅱ,DNA methylation,chromatin histone modification,microRNAs,and long noncoding RNAs.

Single-cell RNA-Seq analysis identified kidney progenitor cells from human urine

Dear Editor,Urine passes through the entire kidney and urinary tract system starting from the glomerulus and ending to the urethra.Cells in the kidney and urinary tract could be exfoliated from the epithelium into the urine,while leukocyte could infiltrate from the local tissue into the urine,which makes the urine a useful subject for clinical evaluation of relevant diseases.