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OBJECTIVES: To identify optimized MRI markers for evaluating chronic kidney disease (CKD) and renal interstitial fibrosis (IF). MATERIALS AND METHODS: This prospective study included 43 patients with CKD and 20 controls. The CKD group was divided into mild and moderate-to-severe subgroups based on pathological results. Scanned sequences included T1 mapping, R2* mapping, intravoxel incoherent motion imaging, and diffusion-weighted imaging. One-way analyses of variance were used to compare MRI parameters among groups. Correlations of MRI parameters with estimated glomerular filtration rate (eGFR) and renal IF were analyzed using age as covariates. The support vector machine (SVM) model was used to evaluate the diagnostic efficacy of multiparametric MRI. RESULTS: Compared to control values, renal cortical apparent diffusion coefficient (cADC), medullary ADC (mADC), cortical pure diffusion coefficient (cDt), medullary Dt (mDt), cortical shifted apparent diffusion coefficient (csADC), and medullary sADC (msADC) values gradually decreased in the mild and moderate-to-severe groups, while cortical T1 (cT1) and medullary T1 (mT1) values gradually increased. Values of cADC, mADC, cDt, mDt, cT1, mT1, csADC, and msADC were significantly associated with eGFR and IF (p < 0.001). The SVM model indicated that multiparametric MRI combining cT1 and csADC can distinguish patients with CKD from controls with high accuracy (0.84), sensitivity (0.70), and specificity (0.92) (AUC: 0.96). Multiparametric MRI combining cT1 and cADC exhibited high accuracy (0.91), sensitivity (0.95), and specificity (0.81) for evaluating IF severity (AUC: 0.96). CONCLUSION: Multiparametric MRI combining T1 mapping and diffusion imaging may be of clinical utility in non-invasive assessment of CKD and IF. CLINICAL RELEVANCE STATEMENT: This study shows that multiparametric MRI combining T1 mapping and diffusion imaging may be clinically useful in the non-invasive assessment of chronic kidney disease (CKD) and interstitial fibrosis; this could provide information for risk stratification, diagnosis, treatment, and prognosis. KEY POINTS: ⢠Optimized MRI markers for evaluating chronic kidney disease and renal interstitial fibrosis were investigated. ⢠Renal cortex/medullary T1 values increased as interstitial fibrosis increased; cortical shifted apparent diffusion coefficient (csADC) correlated significantly with eGFR and interstitial fibrosis. ⢠Support vector machine (SVM) combining cortical T1 (cT1) and csADC/cADC effectively identifies chronic kidney disease and accurately predicts renal interstitial fibrosis.
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Imágenes de Resonancia Magnética Multiparamétrica , Insuficiencia Renal Crónica , Humanos , Estudios Prospectivos , Insuficiencia Renal Crónica/diagnóstico por imagen , Insuficiencia Renal Crónica/patología , Riñón/diagnóstico por imagen , Riñón/patología , Imagen por Resonancia Magnética , Imagen de Difusión por Resonancia Magnética/métodos , FibrosisRESUMEN
OBJECTIVE: The present research analyzed the correlation between N6-methyladenosine (m6A) methylation and ferroptosis associated genes (FAGs) in acute kidney injury (AKI) patients. METHODS: Bioinformatics analysis of microarray profiles (GSE30718) was performed to select differential expression genes (DEGs). FAGs are derived from systematic analysis of the aberrances and functional implications. The m6A methylation related genes were derived from the molecular characterization and clinical significance of m6A modulators. The multi-gene correlation of ferroptosis and M6A methylation modification was displayed. Then, the CIBERSORT algorithm was used to analyze the proportions of 22 immune cell infiltration. RESULTS: In total, 349 DEGs were extracted between the AKI and control samples, among which 172 genes were upregulated and 177 were downregulated. FAGs (SLC1A5, CARS, SAT1, ACSL4, NFE2L2, TFRC, and MT1G) and m6A methylation related genes (YTHDF3, WTAP, and IGF2BP3) were significantly increased in AKI patients (p < 0.05). FAGs (SAT1, ACSL4, and NFE2L2) were positively correlated with the expression level of m6A methylation genes (p < 0.05). NFE2L2 has high diagnostic value, and the level of NFE2L2 was negatively correlated with the degree of follicular helper T (TFH) cell infiltration. CONCLUSION: Our research could provide a new theoretical basis for the pathogenesis and immune mechanism of AKI.
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Lesión Renal Aguda , Ferroptosis , Lesión Renal Aguda/genética , Adenosina/genética , Adenosina/metabolismo , Sistema de Transporte de Aminoácidos ASC/metabolismo , Ferroptosis/genética , Humanos , Metilación , Antígenos de Histocompatibilidad Menor/metabolismoRESUMEN
Renal ischemia/reperfusion (I/R) injury is a major cause of acute kidney injury (AKI), characterized by tubulointerstitial inflammation. Currently, progress in developing effective therapies to prevent or ameliorate AKI by anti-inflammation remains slow. Emerging studies have suggested that NLRP3 (the NOD-, LRR- and pyrin domain-containing 3) inflammasome plays a key role in a wide spectrum of kidney disease models including I/R injury. In this study, we investigated the renal protective effects of A68930, a specific agonist for the D-1 dopamine receptor (DRD1), which was recently recognized to downregulate NLRP3 inflammasome via DRD1 signaling. AKI was induced by renal I/R injury and A68930 was intraperitoneally injected 3 times after renal reperfusion. We showed that A68930 significantly ameliorated renal dysfunction. Meanwhile, A68930 markedly reduced macrophages and T cells infiltration, renal pro-inflammatory cytokines production (TNF-α, IL-6, IL-1ß), serum pro-inflammatory cytokine (TNF-α and IL-6) and NLRP3 inflammasome activation. Additionally, A68930 attenuated I/R-induced mitochondria injury, which was observed by transmission electron microscopy. In summary, our results demonstrated that activation of DRD1 by A68930 inhibited renal and systematic inflammation, and improved kidney function in I/R induced AKI model, which was probably related to the inhibition of the NLRP3 inflammasome activation.
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Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/genética , Cromanos/farmacología , Cromanos/uso terapéutico , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/fisiología , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/metabolismo , Lesión Renal Aguda/etiología , Lesión Renal Aguda/prevención & control , Animales , Modelos Animales de Enfermedad , Regulación hacia Abajo/efectos de los fármacos , Mediadores de Inflamación/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Riñón/metabolismo , Masculino , Ratones Endogámicos C57BL , Daño por Reperfusión/complicaciones , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Neuroinflammation contributes to or even causes central nervous system (CNS) diseases, and its regulation is thus crucial for brain disorders. Mast cells (MCs) and microglia, two resident immune cells in the brain, together with astrocytes, play critical roles in the progression of neuroinflammation-related diseases. MCs have been demonstrated as one of the fastest responders, and they release prestored and newly synthesized mediators including histamine, ß-tryptase, and heparin. However, temporal changes in MC activation in this inflammation process remain unclear. This study demonstrated that MC activation began at 2 h and peaked at 4 h after lipopolysaccharide (LPS) administration. The number of activated MCs remained elevated until 24 h after LPS administration. In addition, the levels of histamine and ß-tryptase in the hippocampus markedly and rapidly increased within 6 h and remained higher than the baseline level within 24 h after LPS challenge. Furthermore, mast cell-deficient KitW-sh/W-sh mice were used to investigate the effects of MCs on microglial and astrocytic activation and blood-brain barrier (BBB) permeability at 4 h after LPS stimulation. Notably, LPS-induced proinflammatory cytokine secretion, microglial activation, and BBB damage were inhibited in KitW-sh/W-sh mice. However, no detectable astrocytic changes were found in WT and KitW-sh/W-sh mice at 4 h after LPS stimulation. Our findings indicate that MC activation precedes CNS inflammation and suggest that MCs are among the earliest participants in the neuroinflammation-initiating events.
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Barrera Hematoencefálica/metabolismo , Lipopolisacáridos/farmacología , Mastocitos/metabolismo , Animales , Barrera Hematoencefálica/efectos de los fármacos , Western Blotting , Ensayo de Inmunoadsorción Enzimática , Heparina/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Histamina/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratas , Ratas Sprague-Dawley , Triptasas/metabolismoRESUMEN
Hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) are orally active first-in-class new generation drugs for renal anemia. This extensive meta-analysis of randomized controlled trials (RCTs) was designed to provide clear information on the efficacy and safety of HIF-PHIs on anemia in chronic kidney disease (CKD) patients. Searches included PubMed, Web of Science, Ovid MEDLINE, and Cochrane Library database up to October 2019. RCTs of patients with CKD comparing HIF-PHIs with erythropoiesis-stimulating agents (ESAs) or placebo in the treatment of anemia. The primary outcome was hemoglobin change from baseline (Hb CFB); the secondary outcomes included iron-related parameters and the occurrence of each adverse event. 26 trials in 17 articles were included, with a total of 2804 dialysis or patients with CKD. HIF-PHIs treatment produced a significant beneficial effect on Hb CFB compared with the placebo group (MD, 0.69; 95% CI, 0.36 to 1.02). However, this favored effect of HIF-PHIs treatment was not observed in subgroup analysis among trials compared with ESAs (MD, 0.06; 95% CI, -0.20 to 0.31). The significant reduction in hepcidin by HIF-PHIs was observed in all subgroups when compared with the placebo group, whereas this effect was observed only in NDD-CKD patients when compared with ESAs. HIF-PHIs increased the risk of nausea (RR, 2.20; 95% CI, 1.06 to 4.53) and diarrhea (RR, 1.75; 95% CI, 1.06 to 2.92). We conclude that orally given HIF-PHIs are at least as efficacious as ESAs treatment to correct anemia short term in patients with CKD. In addition, HIF-PHIs improved iron metabolism and utilization in patients with CKD.
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Anemia/tratamiento farmacológico , Hematínicos/farmacología , Inhibidores de Prolil-Hidroxilasa/administración & dosificación , Insuficiencia Renal Crónica/terapia , Anemia/etiología , Eritropoyetina/metabolismo , Hepcidinas/efectos de los fármacos , Humanos , Prolina Dioxigenasas del Factor Inducible por Hipoxia/antagonistas & inhibidores , Inhibidores de Prolil-Hidroxilasa/efectos adversos , Inhibidores de Prolil-Hidroxilasa/farmacología , Ensayos Clínicos Controlados Aleatorios como Asunto , Diálisis Renal , Insuficiencia Renal Crónica/complicacionesRESUMEN
Artemisinin (Art) is isolated from Artemisia annua L. and known as the most effective antimalaria drugs. Previous studies demonstrated that it could exert an immune-regulatory effect on autoimmune diseases. In this study, we first investigated its potential role in tubulointerstitial inflammation and fibrosis in rats with 5/6 nephrectomy. Subtotal nephrectomized (SNx) rats were orally administered Art (100 mg·kg -1 ·d - 1) for 16 weeks. Blood and urine samples were collected for biochemical examination. Kidney tissues were collected for immunohistochemistry and Western blot analyses. Ang II-induced injury of the human kidney 2 (HK-2) cells was used for in vitro study. It was shown that Art could significantly attenuate the renal function decline in SNx rats compared with control. More importantly, Art treatment significantly reduced the tubulointerstitial inflammation and fibrosis, as demonstrated by the evaluation of renal pathology. Furthermore, Art inhibited the activation of NLRP3 inflammasome and NF-κB in the kidneys. In in vitro study, Art pretreatment could significantly prevent the activation of NLRP3 inflammasome and NF-κB in Ang II-treated HK-2 cells, while BAY11-7082 (an inhibitor of NF-κB) significantly inhibited Ang II-induced NLRP3 inflammasome activation. This study suggested that Art could provide renoprotective role by attenuating the tubulointerstitial inflammation and fibrosis in SNx rats by downregulating the NF-κB/NLRP3 signaling pathway.
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Antiinflamatorios/uso terapéutico , Artemisininas/uso terapéutico , FN-kappa B/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Nefrectomía/efectos adversos , Nefritis Intersticial/tratamiento farmacológico , Nefritis Intersticial/etiología , Animales , Antiinflamatorios/farmacología , Artemisia/química , Artemisininas/farmacología , Línea Celular , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Fibrosis , Humanos , Inflamasomas/efectos de los fármacos , Inflamasomas/metabolismo , Riñón/citología , Riñón/patología , Masculino , Extractos Vegetales/uso terapéutico , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacosRESUMEN
Hypoxia promotes tubulointerstitial inflammation in the kidney. Although hypoxia inducible factor-1α (HIF-1α) is a master regulator of the response to hypoxia, the exact mechanisms through which HIF-1α modulates the induction of tubulointerstitial inflammation are still largely unclear. We demonstrated tubulointerstitial inflammation and increased tubular HIF-1α expression in murine models of ischemia/reperfusion injury and unilateral ureteral obstruction. Increased expression of HIF-1α in tubular epithelial cells was associated with selective shedding of microRNA-23a (miRNA-23a)-enriched exosomes in vivo and systemic inhibition of miRNA-23a prior to ischemia/reperfusion injury attenuated tubulointerstitial inflammation. In vitro, uptake of miRNA-23a-enriched exosomes by macrophages triggered their reprogramming into a pro-inflammatory state via suppression of the ubiquitin editor A20. To confirm the effect of miRNA-23a-containing exosomes on tubulointerstitial inflammation, we exposed tubular epithelial cells to hypoxic conditions to promote the release of miRNA-23a-containing exosomes. Injection of these miRNA-23a-enriched exosomes into uninjured renal parenchyma resulted in increased inflammatory infiltration in vivo. Taken together, our studies demonstrate that the HIF-1α-dependent release of miRNA-23a-enriched exosomes from hypoxic tubular epithelial cells activates macrophages to promote tubulointerstitial inflammation. Blockade of exosome-mediated miRNA-23a transfer between tubular epithelial cells and macrophages may serve as a novel therapeutic approach to ameliorate tubulointerstitial inflammation.
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Células Epiteliales/inmunología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Macrófagos/inmunología , MicroARNs/metabolismo , Nefritis Intersticial/inmunología , Animales , Comunicación Celular/inmunología , Hipoxia de la Célula/genética , Hipoxia de la Célula/inmunología , Reprogramación Celular/genética , Reprogramación Celular/inmunología , Modelos Animales de Enfermedad , Células Epiteliales/citología , Células Epiteliales/metabolismo , Exosomas/inmunología , Exosomas/metabolismo , Regulación de la Expresión Génica/inmunología , Humanos , Túbulos Renales/citología , Túbulos Renales/inmunología , Macrófagos/metabolismo , Masculino , Ratones , Nefritis Intersticial/patología , Transducción de Señal/genética , Transducción de Señal/inmunología , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/genética , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
BACKGROUND: Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease (ESKD) in the world. Emerging evidence has shown that urinary mRNAs may serve as early diagnostic and prognostic biomarkers of DKD. In this article, we aimed to first establish a novel bioinformatics-based methodology for analyzing the "urinary kidney-specific mRNAs" and verify their potential clinical utility in DKD. METHODS: To select candidate mRNAs, a total of 127 Affymetrix microarray datasets of diabetic kidney tissues and other tissues from humans were compiled and analyzed using an integrative bioinformatics approach. Then, the urinary expression of candidate mRNAs in stage 1 study (n = 82) was verified, and the one with best performance moved on to stage 2 study (n = 80) for validation. To avoid potential detection bias, a one-step Taqman PCR assay was developed for quantification of the interested mRNA in stage 2 study. Lastly, the in situ expression of the selected mRNA was further confirmed using fluorescent in situ hybridization (FISH) assay and bioinformatics analysis. RESULTS: Our bioinformatics analysis identified sixteen mRNAs as candidates, of which urinary BBOX1 (uBBOX1) levels were significantly upregulated in the urine of patients with DKD. The expression of uBBOX1 was also increased in normoalbuminuric diabetes subjects, while remained unchanged in patients with urinary tract infection or bladder cancer. Besides, uBBOX1 levels correlated with glycemic control, albuminuria and urinary tubular injury marker levels. Similar results were obtained in stage 2 study. FISH assay further demonstrated that BBOX1 mRNA was predominantly located in renal tubular epithelial cells, while its expression in podocytes and urothelium was weak. Further bioinformatics analysis also suggested that tubular BBOX1 mRNA expression was quite stable in various types of kidney diseases. CONCLUSIONS: Our study provided a novel methodology to identify and analyze urinary kidney-specific mRNAs. uBBOX1 might serve as a promising biomarker of DKD. The performance of the selected urinary mRNAs in monitoring disease progression needs further validation.
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Biología Computacional , Nefropatías Diabéticas/genética , Nefropatías Diabéticas/orina , gamma-Butirobetaína Dioxigenasa/genética , gamma-Butirobetaína Dioxigenasa/orina , Biomarcadores/orina , Bases de Datos Genéticas , Femenino , Humanos , Riñón/metabolismo , Riñón/patología , Masculino , Persona de Mediana Edad , ARN Mensajero/genética , ARN Mensajero/orina , Reproducibilidad de los Resultados , Regulación hacia Arriba/genéticaRESUMEN
IgA nephropathy (IgAN) features variable renal pathology and a heterogeneous clinical course. Our aim was to search noninvasive biomarkers from urinary exosomes for IgAN patients; membrane nephropathy and minimal change disease were included as other glomerulopathy controls. Transmission electron microscopy and nanoparticle tracking analysis confirmed the size and morphology characteristic of urinary exosomes. Exosome markers (Alix and CD63) as well as renal cell markers [aquaporin 2 (AQP2) and nephrin] were detected, which indicate the renal origin of urinary exosomes. Exosome excretion was increased markedly in IgAN patients compared with controls and correlated with levels of proteinuria and tubular injury. More important, urinary exosome excretion correlated with greater histologic activity (mesangial hypercellularity, crescents, and endocapillary hypercellularity). Profiling of the inflammation-related mRNA revealed that exosomal chemokine (C-C motif) ligand 2 (CCL2) was up-regulated in IgAN patients. In a validation study, CCL2 was exclusively highly expressed in IgAN patients compared with healthy controls as well as minimal change disease and membrane nephropathy patients. Also, a correlation between exosomal CCL2 and estimated glomerular filtration rate levels was found in IgAN. Exosomal CCL2 was correlated with tubulointerstitial inflammation and C3 deposition. High CCL2 levels at the time of renal biopsy were associated with subsequent deterioration in renal function. Thus, urinary exosomes and exosomal CCL2 mRNA are promising biomarkers reflecting active renal histologic injury and renal function deterioration in IgAN.
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Biomarcadores/orina , Quimiocina CCL2/orina , Exosomas/metabolismo , Glomerulonefritis por IGA/complicaciones , Inflamación/diagnóstico , Nefritis Intersticial/diagnóstico , ARN Mensajero/metabolismo , Adulto , Estudios de Casos y Controles , Quimiocina CCL2/genética , Exosomas/genética , Femenino , Tasa de Filtración Glomerular , Glomerulonefritis por IGA/patología , Humanos , Inflamación/etiología , Inflamación/orina , Masculino , Nefritis Intersticial/etiología , Nefritis Intersticial/orina , ARN Mensajero/genéticaRESUMEN
Renal fibrosis is the common pathological pathway of progressive CKD. The commonly used biomarkers in clinical practice are not optimal to detect injury or predict prognosis. Therefore, it is crucial to develop novel biomarkers to allow prompt intervention. Urine serves as a valuable resource of biomarker discovery for kidney diseases. Owing to the rapid development of omics platforms and bioinformatics, research on novel urinary biomarkers for renal fibrosis has proliferated in recent years. In this chapter, we discuss the current status and provide basic knowledge in this field. We present novel promising biomarkers including tubular injury markers, proteins related to activated inflammation/fibrosis pathways, CKD273, transcriptomic biomarkers, as well as metabolomic biomarkers. Furthermore, considering the complex nature of the pathogenesis of renal fibrosis, we also highlight the combination of biomarkers to further improve the diagnostic and prognostic performance.
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Biomarcadores/orina , Enfermedades Renales/orina , Riñón/patología , Fibrosis , HumanosRESUMEN
Albuminuria is a key instigator of tubulointerstitial inflammation associated with CKD, but the mechanism through which filtered albumin propagates renal injury remains unclear. In this study, we explored the role in this process of exosome mRNA released from tubular epithelial cells (TECs). Compared with control mice, acute and chronic kidney injury models had more exosomes containing inflammatory cytokine mRNA, particularly the chemokine CCL2, in kidneys and urine. In vitro stimulation of TECs with BSA recapitulated this finding. Notably, the internalization of purified TEC exosomes by cultured macrophages increased if TECs were exposed to BSA. Macrophage internalization of exosomes from BSA-treated TECs led to an enhanced inflammatory response and macrophage migration, but CCL2 silencing in TECs prevented these effects. Using a GFP-CCL2 fusion mRNA construct, we observed direct transfer of CCL2 mRNA from TEC exosomes to macrophages. Mice subjected to tail vein injection of purified BSA-treated TEC exosomes developed tubular injury with renal inflammatory cell infiltration. However, injection of exosomes from BSA-treated CCL2-deficient TECs induced less severe kidney inflammation. Finally, in patients with IgA nephropathy, the increase of proteinuria correlated with augmented urinary excretion of exosomes with exaggerated expression of CCL2 mRNA. Moreover, the level of CCL2 mRNA in urinary exosomes correlated closely with levels of renal interstitial macrophage infiltration in these patients. Our studies demonstrate that the increasing release of exosomes that transfer CCL2 mRNA from TECs to macrophages constitutes a critical mechanism of albumin-induced tubulointerstitial inflammation.
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Lesión Renal Aguda/metabolismo , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Células Epiteliales/metabolismo , Exosomas/metabolismo , Glomerulonefritis por IGA/orina , Túbulos Renales/metabolismo , Macrófagos/metabolismo , ARN Mensajero/metabolismo , Insuficiencia Renal Crónica/metabolismo , Lesión Renal Aguda/genética , Lesión Renal Aguda/orina , Adulto , Animales , Movimiento Celular/efectos de los fármacos , Células Cultivadas , Modelos Animales de Enfermedad , Exosomas/genética , Femenino , Silenciador del Gen , Glomerulonefritis por IGA/complicaciones , Glomerulonefritis por IGA/patología , Humanos , Túbulos Renales/citología , Túbulos Renales/patología , Macrófagos/fisiología , Masculino , Ratones , Persona de Mediana Edad , Nefritis/metabolismo , Nefritis/patología , Proteinuria/etiología , Proteinuria/patología , Proteinuria/orina , Ratas , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/orina , Albúmina Sérica Bovina/farmacología , Adulto JovenRESUMEN
BACKGROUND/AIMS: Chronic kidney disease (CKD) is a worldwide public health problem. Regardless of the underlying primary disease, CKD tends to progress to end-stage kidney disease, resulting in unsatisfactory and costly treatment. Its common pathogenesis, however, remains unclear. The aim of this study was to provide an unbiased catalog of common gene-expression changes of CKD and reveal the underlying molecular mechanism using an integrative bioinformatics approach. METHODS: We systematically collected over 250 Affymetrix microarray datasets from the glomerular and tubulointerstitial compartments of healthy renal tissues and those with various types of established CKD (diabetic kidney disease, hypertensive nephropathy, and glomerular nephropathy). Then, using stringent bioinformatics analysis, shared differentially expressed genes (DEGs) of CKD were obtained. These shared DEGs were further analyzed by the gene ontology (GO) and pathway enrichment analysis. Finally, the protein-protein interaction networks(PINs) were constructed to further refine our results. RESULTS: Our analysis identified 176 and 50 shared DEGs in diseased glomeruli and tubules, respectively, including many transcripts that have not been previously reported to be involved in kidney disease. Enrichment analysis also showed that the glomerular and tubulointerstitial compartments underwent a wide range of unique pathological changes during chronic injury. As revealed by the GO enrichment analysis, shared DEGs in glomeruli were significantly enriched in exosomes. By constructing PINs, we identified several hub genes (e.g. OAS1, JUN, and FOS) and clusters that might play key roles in regulating the development of CKD. CONCLUSION: Our study not only further reveals the unifying molecular mechanism of CKD pathogenesis but also provides a valuable resource of potential biomarkers and therapeutic targets.
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Biología Computacional/métodos , Insuficiencia Renal Crónica/patología , Biomarcadores , Conjuntos de Datos como Asunto , Perfilación de la Expresión Génica , Ontología de Genes , Humanos , Glomérulos Renales/patología , Túbulos Renales/patología , Análisis por Micromatrices , Mapas de Interacción de Proteínas , Insuficiencia Renal Crónica/etiología , Insuficiencia Renal Crónica/genéticaRESUMEN
OBJECTIVE: The objective of this study is to compare the catheter-related complications as well as catheter survival between laparoscopic and traditional surgery in peritoneal dialysis catheter insertion. RESULTS: Five randomized controlled trials and 11 cohort studies were identified. Meta-analysis showed laparoscopic catheter is superior to traditional surgery in terms of controlling catheter migration (OR 0.17, 95% CI 0.08-0.33; p < 0.00001) and catheter survival rate (1-year survival rate: OR 3.05, 95% CI 1.72-5.41, p = 0.0001; 2-year survival rate: OR 2. 07, 95% CI 1.29-3.33, p = 0.0001), but slightly increases the risk of bleeding (OR 2.13, 95% CI 1.07-4.23, p = 0.03). The two groups were not significantly different in other catheter-related complications. As regards the quality of the analysis, only the migration analysis ranked A-level, while the rest fell into Class B or C. The overall research quality was moderate. CONCLUSION: Laparoscopic surgery is superior to traditional surgery on reducing catheter migration and prolonging catheter survival rate according to our analysis.
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Infecciones Relacionadas con Catéteres/etiología , Fallo Renal Crónico/terapia , Laparoscopía , Diálisis Peritoneal , Implantación de Prótesis , Catéteres de Permanencia/efectos adversos , Investigación sobre la Eficacia Comparativa , Análisis de Falla de Equipo , Humanos , Laparoscopía/efectos adversos , Laparoscopía/métodos , Diálisis Peritoneal/instrumentación , Diálisis Peritoneal/métodos , Implantación de Prótesis/efectos adversos , Implantación de Prótesis/métodosRESUMEN
BACKGROUND: M-type phospholipase A2 receptor (PLA2R) is the major autoantigen in adult idiopathic membranous nephropathy (IMN). Although reactive epitopes in the PLA2R domains have been identified, the clinical value of these domains recognized by anti-PLA2R antibodies remains controversial. Accordingly, this study aimed to quantitatively detect changes in the concentrations of different antibodies against epitopes of PLA2R in patients with IMN before and after treatment to evaluate the clinical value of epitope spreading. METHODS: Highly sensitive time-resolved fluorescence immunoassay was used to quantitatively analyze the concentrations of specific IgG and IgG4 antibodies against PLA2R and its epitopes (CysR, CTLD1, CTLD6-7-8) in a cohort of 25 patients with PLA2R-associated membranous nephropathy (13 and 12 in the remission and non-remission groups, respectively) before and after treatment, and the results were analyzed in conjunction with clinical biochemical indicators. RESULTS: The concentration of specific IgG (IgG4) antibodies against PLA2R and its epitopes (CysR, CTLD1 and CTLD6-7-8) in non-remission group was higher than that in remission group. The multipliers of elevation of IgG (IgG4) antibody were 5.6(6.2) fold, 3.0(24.3) fold, 1.6(9.0) fold, and 4.2(2.6) fold in the non-remission/remission group, respectively. However, the difference in antibody concentrations between the two groups at the end of follow-up was 5.6 (85.2), 1.7 (13.1), 1.0 (5.1), and 1.5 (22.3) times higher, respectively. When detecting concentrations of specific IgG antibodies against PLA2R and its different epitopes, the remission rate was 66.67% for only one epitope at M0 and 36.36% for three epitopes at M0. When detecting concentrations of specific IgG4 antibodies against PLA2R and its different epitopes, the remission rate was 100.00% for only one epitope at M0 and 50.00% for three epitopes at M0. A trivariate logistic regression model for the combined detection of eGFR, anti-CTLD678 IgG4, and urinary protein had an AUC of 100.00%. CONCLUSION: Low concentrations of anti-CysR-IgG4, anti-CTLD1-IgG4, and anti-CTLD6-7-8-IgG4 at initial diagnosis predict rapid remission after treatment. The use of specific IgG4 against PLA2R and its different epitopes combined with eGFR and urinary protein provides a better assessment of the prognostic outcome of IMN.
Asunto(s)
Glomerulonefritis Membranosa , Ricina , Adulto , Humanos , Cisteína , Pronóstico , Receptores de Fosfolipasa A2 , Lectinas Tipo C , Epítopos , Inmunoglobulina GRESUMEN
BACKGROUND: M-type phospholipase A2 receptor (PLA2R) is a major auto-antigen of primary membranous nephropathy(PMN). Anti-PLA2R antibody levels are closely associated with disease severity and therapeutic effectiveness. Analysis of PLA2R antigen epitope reactivity may have a greater predictive value for remission compared with total PLA2R-antibody level. This study aims to elucidate the relationship between domain-specific antibody levels and clinical outcomes of PMN. METHODS: This retrospective analysis included 87 patients with PLA2R-associated PMN. Among them, 40 and 47 were treated with rituximab (RTX) and cyclophosphamide (CTX) regimen, respectively. The quantitative detection of -immunoglobulin G (IgG)/-IgG4 targeting PLA2R and its epitope levels in the serum of patients with PMN were obtained through time-resolved fluorescence immunoassays and served as biomarkers in evaluating the treatment effectiveness. A predictive PMN remission possibility nomogram was developed using multivariate logistic regression analysis. Discrimination in the prediction model was assessed using the area under the receiver operating characteristic curve (AUC-ROC).Bootstrap ROC was used to evaluate the performance of the prediction model. RESULTS: After a 6-month treatment period, the remission rates of proteinuria, including complete remission and partial remission in the RTX and CTX groups, were 70% and 70.21% (P = 0.983), respectively. However, there was a significant difference in immunological remission in the PLA2R-IgG4 between the RTX and CTX groups (21.43% vs. 61.90%, P = 0.019). Furthermore, we found differences in PLA2R-CysR-IgG4(P = 0.030), PLA2R-CTLD1-IgG4(P = 0.005), PLA2R-CTLD678-IgG4(P = 0.003), and epitope spreading (P = 0.023) between responders and non-responders in the CTX group. Multivariate logistic analysis showed that higher levels of urinary protein (odds ratio [OR], 0.49; 95% confidence interval [CI], 0.26-0.95; P = 0.035) and higher levels of PLA2R-CTLD1-IgG4 (OR, 0.79; 95%CI,0.62-0.99; P = 0.041) were independent risk factors for early remission. A multivariate model for estimating the possibility of early remission in patients with PMN is presented as a nomogram. The AUC-ROC of our model was 0.721 (95%CI, 0.601-0.840), in consistency with the results obtained with internal validation, for which the AUC-ROC was 0.711 (95%CI, 0.587-0.824), thus, demonstrating robustness. CONCLUSIONS: Cyclophosphamide can induce immunological remission earlier than rituximab at the span of 6 months. The PLA2R-CTLD1-IgG4 has a better predict value than total PLA2R-IgG for remission of proteinuria at the 6th month.
Asunto(s)
Autoanticuerpos , Glomerulonefritis Membranosa , Receptores de Fosfolipasa A2 , Inducción de Remisión , Rituximab , Humanos , Glomerulonefritis Membranosa/tratamiento farmacológico , Glomerulonefritis Membranosa/inmunología , Glomerulonefritis Membranosa/sangre , Receptores de Fosfolipasa A2/inmunología , Masculino , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Rituximab/uso terapéutico , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Adulto , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Ciclofosfamida/uso terapéutico , Anciano , Curva ROC , Resultado del TratamientoRESUMEN
Epidemiological data suggest that individuals in all stages of chronic kidney disease (CKD) have higher risks of developing cognitive impairment. The relationship between CKD and cognition has been assessed exclusively using glomerular function markers; however, kidney tubule injury has not been assessed. We assessed the association between urinary biomarkers of renal tubular injury and cognitive dysfunction in older patients with CKD Stages 3-4. According to the Montreal Cognitive Assessment, participants were divided into cognitive dysfunction and control groups. Compared with the control group, the cognitive dysfunction group had significantly higher percentages of smokers, noticeably lower average education, and higher mitochondrial DNA (mtDNA) levels in the peripheral blood. Spearman correlation analysis showed that higher urine neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, and beta-2 microglobulin (ß2M) levels were significantly associated with lower cognitive scores. Multivariate logistic regression analysis showed that only increased urinary ß2M levels were independently associated with cognitive worsening in CKD after adjusting for confounders. Logistic regression identified a promising role of urinary ß2M combined with smoking and education for predicting cognitive impairment in CKD. Urinary ß2M and cognitive function negatively correlated with mtDNA content, suggesting that mitochondrial dysfunction is a common pathophysiological mechanism linking CKD and cognitive dysfunction.
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[This corrects the article DOI: 10.7150/thno.33520.].
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Objective: This study aims to explore the correlation between ferroptosis and immune microenvironment (IME) in diabetic kidney disease (DKD) to provide a new clue for exploring the underlying molecular mechanisms. Methods: Corresponding RNA data of DKD patients were downloaded from GEO databases. The weighted gene co-expression network analysis (WGCNA) was used to construct the network, and the selected hub genes, then, overlapped with ferroptosis-related genes (FRGs) from FerrDb. Consensus clustering was performed to identify new molecular subgroups. ESTIMATE, TIMER and ssGSEA analyses were applied to determinate the IME and immune status. Functional analyses including GO, KEGG and GSEA were conducted to elucidate the underlying mechanisms. Results: Two molecular subtypes were identified based on the expression of FRGs. ESTIMATE algorithm revealed that there were significant differences in ESTIMATE score between these two clusters of DKD patients, with no significant difference found in stromal score and immune score. In addition, TIMER algorithm indicated there was a significant difference in the degree of T cell infiltration. The ssGSEA algorithm showed immunity was mainly concentrated in thick ascending limb and distal convoluted tubule in adult kidney. GO, KEGG and GSEA analyses revealed that the differentially expressed genes (DEGs) were mainly enriched in immune and metabolism associated pathways. Conclusion: The ferroptosis may be induced by dysregulation of IME, thereby accelerating the progression of DKD. Our work could be applied to provide a new clue for exploring the underlying molecular mechanisms and sheds novel light on the therapy strategy of DKD.
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Background: Postoperative cognitive dysfunction (POCD) is a common complication characterized by a significant cognitive decline. Increasing evidence suggests an association between the pathogenesis of POCD and Alzheimer's disease (AD). However, a comprehensive understanding of their relationships is still lacking. Methods: First, related databases were obtained from GEO, ArrayExpress, CNGB, and DDBJ repositories. De novo analysis was performed on the raw data using a uniform bioinformatics workflow. Then, macro- and micro-level comparisons were conducted between the transcriptomic changes associated with AD and POCD. Lastly, POCD was induced in male C57BL/6j mice and the hippocampal expression levels of mRNAs of interest were verified by PCR and compared to those in AD congenic models. Results: There was a very weak correlation in the fold-changes in protein-coding transcripts between AD and POCD. Overall pathway-level comparison suggested that AD and POCD are two disease entities. Consistently, in the classical AD pathway, the mitochondrial complex and tubulin mRNAs were downregulated in both the POCD hippocampus and cortex. POCD and AD hippocampi might share the same pathways, such as tryptophan metabolism, but undergo different pathological changes in phagosome and transferrin endocytosis pathways. The core cluster in the hippocampal network was mainly enriched in mitosis-related pathways. The hippocampal expression levels of genes of interest detected by PCR showed good consistency with those generated by high throughput platforms. Conclusion: POCD and AD are associated with different transcriptomic changes despite their similar clinical manifestations. This study provides a valuable resource for identifying biomarkers and therapeutic targets for POCD.