LncNFYB promotes the proliferation of rheumatoid arthritis fibroblast-like synoviocytes via LncNFYB/ANXA2/ERK1/2 axis.

Long noncoding RNAs (lncRNAs) are specifically expressed in different diseases and regulate disease progression. To explore the functions of rheumatoid arthritis (RA)-specific lncRNA, we determined the lncRNA expression profile of fibroblast-like synoviocytes (FLS) obtained from patients with RA and osteoarthritis (OA) using a LncRNA microarray and identified up-regulated LncNFYB in RA as a potential therapeutic target. Using gain- and loss-of-function studies, LncNFYB was proven to promote FLS proliferation and cell cycle progress but not affect their invasion, migration, and apoptotic abilities. Further investigation discovered that LncRNA could combine with annexin A2 (ANXA2) and enhance the level of phospho-ANXA2 (Tyr24) in the plasma membrane area, which induced the activation of ERK1/2 to promote proliferation. These findings provide new insights into the biological functions of LncNFYB on modification of FLS, which may be exploited for the therapy of RA.

Association between serum uric acid level and systemic lupus erythematosus kidney outcome: An observational study in Southern Chinese population and a meta-analysis.

OBJECTIVE: The study aimed to explore the effect of serum uric acid (SUA) level on the progression of kidney function in systemic lupus erythematosus (SLE) patients. METHODS: A total of 123 biopsy-proven lupus nephritis (LN) patients were included in this retrospective observational study. Cox proportional hazard regression analyses as well as restricted cubic spline analyses were performed to identify predictors of renal outcome in LN patients. We also performed a systematic review and meta-analysis for SUA and overall kidney outcomes in SLE patients. RESULTS: Based on the laboratory tests at renal biopsy, 72 (58.5%) of the 123 patients had hyperuricemia. The median (IQR) follow-up duration was 3.67 years (1.79-6.63 years), and a total of 110 (89.4%) patients experienced progression of LN. Increased serum uric acid level, whether analyzed as continuous or categorical variable, was associated with higher risk of LN progression in Cox proportional hazard regression model (hazard ratio [HR]: 1.003, 95% confidence interval [CI]: 1.001-1.005; HR: 1.780, 95% CI: 1.201-2.639, respectively). This relationship maintained in women (HR: 1.947, 95% CI: 1.234-3.074) but not men (HR: 2.189, 95% CI: 0.802-5.977). The meta-analysis showed a similar result that both continuous and categorical SUA were positively associated with the risk of kidney function progression in LN (weighted mean difference [WMD]: 1.73, 95% CI: 0.97-2.49; odds ratio [OR]: 1.55, 95% CI: 1.20-2.01, respectively). CONCLUSIONS: Our study found overall and especially in women that higher SUA in LN patients were associated with increased risk of renal progression. Meta-analysis yielded consistent results. Future studies are required to establish if uric acid can be used as a biomarker for risk assessment and/or as a novel therapeutic target in SLE.

Negative regulation of amino acid signaling by MAPK-regulated 4F2hc/Girdin complex.

Amino acid signaling mediated by the activation of mechanistic target of rapamycin complex 1 (mTORC1) is fundamental to cell growth and metabolism. However, how cells negatively regulate amino acid signaling remains largely unknown. Here, we show that interaction between 4F2 heavy chain (4F2hc), a subunit of multiple amino acid transporters, and the multifunctional hub protein girders of actin filaments (Girdin) down-regulates mTORC1 activity. 4F2hc interacts with Girdin in mitogen-activated protein kinase (MAPK)- and amino acid signaling-dependent manners to translocate to the lysosome. The resultant decrease in cell surface 4F2hc leads to lowered cytoplasmic glutamine (Gln) and leucine (Leu) content, which down-regulates amino acid signaling. Consistently, Girdin depletion augments amino acid-induced mTORC1 activation and inhibits amino acid deprivation-induced autophagy. These findings uncovered the mechanism underlying negative regulation of amino acid signaling, which may play a role in tightly regulated cell growth and metabolism.

Prediabetes and structural brain abnormalities: Evidence from observational studies.

Type 2 diabetes mellitus has been linked to structural brain abnormalities, but evidence of the association among prediabetes and structural brain abnormalities has not been systematically evaluated. Comprehensive searching strategies and relevant studies were systematically retrieved from PubMed, Embase, Medline and web of science. Twelve articles were included overall. Stratified analyses and regression analyses were performed. A total of 104 468 individuals were included. The risk of infarct was associated with continuous glycosylated haemoglobin (HbA1c ) [adjusted odds ratio (OR) 1.19 (95% confidence interval [CI]: 1.05-1.34)], or prediabetes [adjusted OR 1.13 (95% CI: 1.00-1.27)]. The corresponding ORs associated with white matter hyperintensities were 1.08 (95%CI: 1.04-1.13) for prediabetes, and 1.10 (95%CI: 1.08-1.12) for HbA1c . The association was significant between the decreased risk of brain volume with continuous HbA1c (the combined OR 0.92, 95% CI: 0.87-0.98). Grey matter volume and white matter volume were inversely associated with prediabetes [weighted mean deviation (WMD), -9.65 (95%CI: -15.25 to -4.04) vs WMD, -9.25 (95%CI: -15.03 to -3.47)]. There were no significant association among cerebral microbleeds, hippocampal volume, continuous total brain volume, and prediabetes. Our findings demonstrated that (a) both prediabetes and continuous HbA1c were significantly associated with increasing risk of infarct or white matter hyperintensities; (b) continuous HbA1c was associated with a decreased risk of brain volume; (c) prediabetes was inversely associated with grey matter volume and white matter volume. To confirm these findings, further studies on early diabetes onset and structural brain abnormalities are needed.

Cytoplasm protein GFAP magnetic beads construction and application as cell separation target for brain tumors.

BACKGROUND: It is very important to develop a highly efficient cerebrospinal fluid (CSF) detection system with diagnosis and prediction function, for which the detection of circulating tumor cells (CTCs) in CSF is a good choice. In contrast to the past use of epithelial EpCAM as CTCs separation target, a cytoplasm protein of GFAP antibody was first selected to construct highly-sensitive immunomagnetic liposome beads (IMLs). The validation and efficiency of this system in capturing CTCs for brain tumors were measured both in vitro and in vivo. The associations between the numbers of CTCs in patients with their clinical characteristics were further analyzed. RESULTS: Our data show that CTCs can be successfully isolated from CSF and blood samples from 32 children with brain tumors. The numbers of CTCs in CSF were significantly higher than those in blood. The level of CTCs in CSF was related to the type and location of the tumor rather than its stage. The higher the CTCs number is, the more possibly the patient will suffer from poor prognosis. Genetic testing in GFAP CTC-DNA by sanger sequencing, q-PCR and NGS methods indicated that the isolated CTCs (GFAP+/EGFR+) are the related tumor cell. For example, the high expression of NPR3 gene in CSF CTCs was consistent with that of tumor tissue. CONCLUSIONS: The results indicated that GFAP-IML CTCs isolation system, combined with an EGFR immunofluorescence assay of antitumor marker, can serve as a brand-new method for the identification of CTCs for brain tumors. Via lumbar puncture, a minimally invasive procedure, this technique may play a significant role in the clinical diagnosis and drug evaluation of brain tumors.

Urine NGAL as an early biomarker for diabetic kidney disease: accumulated evidence from observational studies.

Objectives: Urine neutrophil gelatinase-associated lipocalin (NGAL) was found to increase in diabetic kidney disease (DKD). However, the clinical value of urine NGAL as diagnostic indicators in DKD remains to be clarified. Methods: Relevant studies were systematically retrieved from PubMed, Embase, Web of Science, and the Cochrane Library. Stratified analyses and regression analyses were performed. Results: Fourteen studies with 1561 individuals were included in our analysis, including 1204 cross-sectional participants and 357 cohort participants. For the cross-sectional studies, the pooled sensitivity and specificity of NGAL in the diagnosis of DKD were 0.82 (95% confidence interval (CI): 0.75-0.87) and 0.81 (95% CI: 0.68-0.90), respectively. The pooled diagnostic odds ratio was 19 (95% CI: 11-33), and the overall area under the curve was 0.88 (95% CI: 0.84-0.90). For the cohort studies, the pooled sensitivity and specificity of NGAL in the diagnosis of DKD were 0.96 (95% CI: 0.91-0.98) and 0.89 (95% CI: 0.84-0.92), respectively. The overall area under the curve was 0.98, indicating good discriminative ability of NGAL as biomarkers for DKD. Conclusions: Urine NGAL, as the early diagnostic marker of DKD, might have the high diagnostic value, especially in cohort studies.

Significance of perivascular tumour cells defined by CD109 expression in progression of glioma.

In the progression of glioma, tumour cells often exploit the perivascular microenvironment to promote their survival and resistance to conventional therapies. Some of these cells are considered to be brain tumour stem cells (BTSCs); however, the molecular nature of perivascular tumour cells has not been specifically clarified because of the complexity of glioma. Here, we identified CD109, a glycosylphosphatidylinositol-anchored protein and regulator of multiple signalling pathways, as a critical regulator of the progression of lower-grade glioma (World Health Organization grade II/III) by clinicopathological and whole-genome sequencing analysis of tissues from human glioma. The importance of CD109-positive perivascular tumour cells was confirmed not only in human lower-grade glioma tissues but also in a mouse model that recapitulated human glioma. Intriguingly, BTSCs isolated from mouse glioma expressed high levels of CD109. CD109-positive BTSCs exerted a proliferative effect on differentiated glioma cells treated with temozolomide. These data reveal the significance of tumour cells that populate perivascular regions during glioma progression, and indicate that CD109 is a potential therapeutic target for the disease. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Polymorphisms of insulin receptor substrate 2 are putative biomarkers for pediatric medulloblastoma: considering the genetic susceptibility and pathological diagnoses.

Molecular profiling subgrouped medulloblastoma (MB) into four subtypes featured by distinct footprints. However, germline studies on genetic susceptibility in Chinese population have not been reported. To investigate the correlation of polymorphisms involved in the AKT signaling pathway with clinicopathological parameters in pediatric MB, and their contribution to the clinical outcome, we performed a case-controlled cohort consisting of 48 patients with pediatric MB and 190 healthy controls from Han population. Significant association in rs7987237 of insulin receptor substrate 2 (IRS2) was identified as risk allele/genotype between MB patients and control group (P<0.05). The allele "C" of rs7987237 in IRS2 gene was associated with an increased risk of MB (P=0.025; OR=2.95, 95%CI 1.43-6.11) after Bonferroni correction. Among 48 patients, various genotypes of rs7987237 show significant association with pathological diagnosis and metastases risk (P<0.05). Furthermore, the survival curve of patients with genotype "CC" of rs7987237 was confirmed with better outcome (P<0.001). Combined with previous results, our study suggests that polymorphisms of IRS2 putatively participated in the development of pediatric MB development. Therefore, it may benefit the early diagnosis and indicate the prognosis of patients with MB in Han population.

Glioma risks associate with genetic polymorphisms of XRCC1 gene in Chinese population.

Glioma is the most common type of primary brain tumors in adults. Previous evidence indicates that the X-ray repair cross-complementing group 1 gene (XRCC1) is an important candidate gene which influencing the pathogenesis of glioma. This study aims to assess the potential associations between glioma risks and genetic polymorphisms of XRCC1 gene. A total of 1,286 Chinese Han ethnic subjects consisting of 638 glioma patients and 648 controls were recruited in this case-control study. The genotyping of XRCC1 genetic polymorphisms (c.482C>T, c.1161G>A, and c.1804C>A) were conducted using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), created restriction site-PCR (CRS-PCR) and DNA sequencing methods. Our data indicated that the allelic and genotypic frequencies of these genetic polymorphisms in glioma patients were significantly different from those of controls. We detected that the alleles/genotypes were statistically associated with the increased risks of glioma (for c.482C>T, TT versus (vs.) CC: OR = 2.24, 95% CI = 1.48-3.39, P < 0.001; T vs. C: OR = 1.30, 95% CI = 1.09-1.53, P = 0.003; for c.1161G>A, AA vs. GG: OR = 1.62, 95% CI = 1.11-2.35, P = 0.012; A vs. G: OR = 1.19, 95% CI = 1.01-1.41, P = 0.040; for c.1804C>A, AA vs. CC: OR = 2.12, 95% CI = 1.45-3.11, P < 0.001; A vs. C: OR = 1.32, 95% CI = 1.12-1.56, P = 0.001). Our findings suggest that these genetic polymorphisms of XRCC1 gene may influence glioma risks in Chinese Han ethnic subjects, and might be potential molecular markers for evaluating glioma risks.

CARMA3 is overexpressed in human glioma and promotes cell invasion through MMP9 regulation in A172 cell line.

Caspase recruitment domain-containing membrane-associated guanylate kinase protein 10 or CARMA3 (CARD10) is a recently characterized oncoprotein involved in the progression of several human malignancies. The present study aims to investigate the expression pattern and biological roles of CARMA3 protein in human glioma. CARMA3 expression was analyzed in 97 glioma specimens using immunohistochemistry. We observed negative staining in normal astrocytes and positive staining of CARMA3 in 25 out of 97 (25.8%) glioma samples. Overexpression of CARMA3 correlated with tumor grade (p < 0.001). Small interfering RNA knockdown was performed in A172 cell line with relatively high CARMA3 expression. Using colony formation assay and Matrigel invasion assay, we showed that CARMA3 depletion in A172 cell line inhibited cell proliferation and cell invasion. In addition, mRNA and protein levels of matrix metallopeptidase 9 (MMP9) were downregulated, indicating CARMA3 might regulate invasion through MMP9. In conclusion, CARMA3 serves as an oncoprotein in human glioma by regulating cell invasion, possibly through MMP9 regulation.

Evaluation of osteopontin as a potential biomarker for central nervous system embryonal tumors.

Osteopontin (OPN) is a protein linked to tumor growth, progression and metastasis of cancers. However, its role in the progression of central nervous system (CNS) embryonal tumors such as atypical teratoid/rhabdoid tumor (AT/RT), medulloblastoma (MB) and primitive neuroepithelial tumors (PNET) remains elusive. In this study, we investigated the value of OPN staining in differential diagnosis of AT/RT from MB and PNET, and assessed the correlation between OPN expression and patients' prognosis. This retrospective study was conducted on tissue sections obtained from children cases with CNS embryonal tumors treated in Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine from 2006 to 2012 by immunohistochemistry (IHC). 49 cases were collected (11 AT/RTs, 25 MBs, and 13 PNETs), with a median follow-up time of 28.9 months. OPN expression in AT/RT was significantly higher than MB and PNET with the positive rates of 100, 32, and 23 %, respectively (P < 0.01). The specificity and sensitivity of OPN staining in diagnosing AT/RT are 97.4 and 90.9 %, respectively, as judged by strong OPN IHC staining level (+++). Patients who had positive OPN staining have increased risks of poorer median overall survival (hazard risk 5.54, 95 % CI 1.87-16.38) and tumor progression (hazard risk 14.47, 95 % CI 4.47-46.85). OPN is a valuable biomarker to aid in the differential diagnosis between AT/RT and MB/PNET. Moreover, OPN is a potential novel prognostic marker for CNS embryonal tumors.

Diabetic Retinopathy and Brain Structure, Cognition Function, and Dementia: A Bidirectional Mendelian Randomization Study.

BACKGROUND: Accumulating evidence has demonstrated that hyperglycemia is a possible risk factor for mild cognitive impairment or Alzheimer's disease. Diabetic retinopathy (DR) has been identified as a risk factor for dementia in patients with diabetes. OBJECTIVE: This study aimed to investigate the causal relationships between DR and brain structure, cognitive function, and dementia. METHODS: We performed bidirectional two-sample Mendelian randomization for DR, brain structure, cognitive function, and dementia using the inverse-variance weighted method. RESULTS: Inverse-variance weighted analysis showed the association of DR with vascular dementia (OR = 1.68, 95% CI: 1.01-2.82), and dementia was significantly associated with the increased risk of non-proliferative DR (NPDR) (OR = 1.76, 95% CI: 1.04-2.98). Furthermore, better cognitive performance was significantly associated with a reduced risk of NPDR (OR = 0.85, 95% CI: 0.74-0.98). No association was observed between DR and brain structure. CONCLUSIONS: These findings suggest that the association of DR with vascular dementia. The reciprocal effect of cognitive performance and dementia on NPDR risk highlights the potential benefits of dementia prevention for reducing the burden of DR.

Cancer Stem Cells in Tumours of the Central Nervous System in Children: A Comprehensive Review.

Cancer stem cells (CSCs) are a subgroup of cells found in various kinds of tumours with stem cell characteristics, such as self-renewal, induced differentiation, and tumourigenicity. The existence of CSCs is regarded as a major source of tumour recurrence, metastasis, and resistance to conventional chemotherapy and radiation treatment. Tumours of the central nervous system (CNS) are the most common solid tumours in children, which have many different types including highly malignant embryonal tumours and midline gliomas, and low-grade gliomas with favourable prognoses. Stem cells from the CNS tumours have been largely found and reported by researchers in the last decade and their roles in tumour biology have been deeply studied. However, the cross-talk of CSCs among different CNS tumour types and their clinical impacts have been rarely discussed. This article comprehensively reviews the achievements in research on CSCs in paediatric CNS tumours. Biological functions, diagnostic values, and therapeutic perspectives are reviewed in detail. Further investigations into CSCs are warranted to improve the clinical practice in treating children with CNS tumours.

[Research on the relationship between levels of soluble cluster of differentiation 40 ligand, matrix metalloproteinase 9 and pregnancy-associated plasma protein A in serum and stability of carotid plaques].

OBJECTIVES: To study the relationship between serum levels of some inflammatory markers and stability of carotid plaques in the patients with carotid plaques and evaluate the ability of each serum marker in identifying vulnerable carotid plaques. METHODS: The study included 65 consecutive patients with carotid plaques confirmed by imaging examinations from March 2008 to March 2010. All the patients were classified as stable plaques group (n = 21) and unstable plaques group (n = 44) according to the characteristic findings of the plaques in MRI such as the thickness of fibrous cap, the existence of large lipid core and the intra-plaque hemorrhage. The patients of unstable plaques group were further classified as unruptured plaques group (n = 29) and rupture plaques group (n = 15) according to the integrity of fibrous cap. Serum levels of soluble cluster of differentiation 40 ligand (sCD40L), matrix metalloproteinase 9 (MMP-9) and pregnancy-associated plasma protein A (PAPP-A) were determined by ELISA. RESULTS: Serum levels of sCD40L and MMP-9 in patients of unstable plaques group, unruptured plaques group and rupture plaques group were all significantly enhanced compared to individuals of stable plaques group (SCD40L: χ(2) = 6.45, 12.04 and 16.23, P < 0.01; MMP-9; F = 2.55, 5.10 and 4.69, P < 0.05). Serum levels of PAPP-A in patients of unstable plaques group and rupture plaques group were all significantly enhanced compared to individuals of stable plaques group (χ(2) = 11.71 and 13.55, P < 0.05). Serum levels of PAPP-A in patients of rupture plaques group were significantly enhanced compared to individuals of unruptured plaques group (χ(2) = 13.19, P = 0.000). sCD40L ≥ 673.22 ng/L (OR = 22.47, 95%CI: 2.11 - 239.81, P = 0.010), MMP-9 ≥ 84.09 µg/L (OR = 10.01, 95%CI: 1.74 - 57.78, P = 0.010) and PAPP-A ≥ 0.101 µg/L (OR = 14.29, 95%CI: 2.69 - 75.90, P = 0.002) were all significantly correlated with the vulnerability of carotid plaques. CONCLUSIONS: There appear to be a relationship between the serum levels of sCD40L, MMP-9 and PAPP-A and the stability of carotid plaques in patients with carotid plaques. High serum levels of the above-mentioned markers may indicate that the plaques were vulnerable or ruptured.

Establishment and verification of a prognostic model of liver cancer by RNA-binding proteins based on the TCGA database.

Background: Globally, liver cancer is one of the most common malignant tumors and is the third leading cause of cancer deaths. RNA-binding protein (RBP) is a general term for a class of proteins that bind to RNA to regulate metabolic processes. The expression of RNA-binding proteins is related to the prognosis of liver cancer patients. Methods: The RBP gene expression data of liver cancer were extracted from the TCGA database. First, the differentially expressed RBPs (DE RBPs) were selected through enrichment analysis and volcano mapping. Then, the prognosis-related RBP genes were selected through single-factor Cox regression analysis. The key prognosis-related RBPs were further screened by multifactor Cox regression analysis, and a formula for the patient's risk coefficient was obtained. Finally, based on the patient's risk score, a nomogram was established and verified. Results: We extracted 374 cancer tissue samples and 50 normal tissue samples with the clinical information from each sample. Through enrichment analysis, we screened 208 upregulated RBPs and 122 downregulated RBPs. Prognosis-related high-risk genes were EEF1E1, NOP56, UPF3B, SF3B4, SMG5, CD3EAP, BRCA1, BARD1, XPO5, CSTF2, EZH2, EXO1, RRP12, PRIM1, LIN28B, NROB1 and TCOF1, and the low-risk genes were MRPL46, RCL1, MRPL54, CPEB3, IFIT5, PPARGC1A, EIF2AK4, SEPSECS, ACO1, SECISBP2 L and ZCCHC24. Further multivariate Cox regression analysis was performed on the prognosis-related RBPs, and the three key prognosis-related RBPs were screened out, which were BARD1, NR0B1 and EIF2AK4. A patient risk coefficient calculation formula was obtained: risk score = (1.207×BARD1 Exp) + (0.483×NR0B1 Exp) + (-0.720×EIF2AK4 Exp). Finally, a nomogram was established based on the risk score to predict the survival time of patients from 1 to 5 years. Conclusions: The nomogram has good predictive value for the survival time of liver cancer patients.

＜Editors' Choice＞ Advantages of gasless single-port transumbilical extracorporeal laparoscopic-assisted appendectomy in the treatment of uncomplicated acute appendicitis in children in China: a multi-institutional retrospective study.

Gasless transumbilical extracorporeal laparoscopic-assisted appendectomy is an approach used increasingly to treat uncomplicated acute appendicitis (UAA). However, there is limited information on its clinical effects and value in the Chinese pediatric population. This study retrospectively reviewed patients with UAA treated in two pediatric institutions from January 2018 through October 2021. Enrolled patients were divided into two groups by operative technique: gasless transumbilical laparoscopic-assisted appendectomy (gasless-TULAA, n=142) and conventional laparoscopic appendectomy (CLA, three-port, n=126). The perioperative clinical data, including age, sex, body mass index (BMI), operation time, time to postoperative ambulation, time to first postoperative exhaust, hospitalization expenses, and postoperative complications (incision infection, intestinal obstruction, and residual abdominal abscess), were compared between the two groups. Operations in both groups were successfully conducted without converting to open surgery. There were no significant differences (p > 0.05) in age and BMI in the two groups. Compared with CLA, gasless-TULAA showed significantly shorter operation time, earlier postoperative ambulation, shorter postoperative exhaust time, and lower hospital cost (p < 0.001). All patients were followed for 3 months, and postoperative complications were observed in three patients: two patients in the gasless-TULAA group (one with surgical wound effusion, one with intra-abdominal abscess), and one patient in the CLA group (surgical wound infection); there was no significant difference between the groups. Notably, 38 patients initially treated by gasless-TULAA were converted because of intraoperative factors. The gasless-TULAA technique had potential benefits: shortened operation time, better outcome, and greater cost-efficiency. These superiorities are worthy of future large-scale prospective study.

Association of kidney function and brain health: A systematic review and meta-analysis of cohort studies.

OBJECTIVE: This study aimed to evaluate the bidirectional association between the kidney dysfunction and the brain health, including structural and functional abnormalities. DESIGN: Systematic review and meta-analysis with network meta-analysis for outcomes with different estimated glomerular filtration rate (eGFR) ranges. DATA SOURCES: PubMed, Embase database, Cochrane library and Web of Science (up to Dec. 2021). ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Longitudinal studies that provided evidence of the impact of kidney function estimated from eGFR and urine albumin-to-creatinine ratio (UACR) or chronic kidney disease (CKD) on structural and functional brain abnormalities, and those that provided evidence of the opposite relationship. Studies with study population mean age under 18 years old were excluded. MAIN OUTCOME MEASURES: Two independent reviewers screened the included studies, extracted the data, and assessed the risk of bias. We performed a random-effects meta-analysis and a network meta-analysis for outcomes with compatible data. We assessed the risk of bias using the Newcastle-Ottawa Quality Assessment Scale criteria (NOS). Subgroup and sensitivity analyses were conducted to explore heterogeneity in the meta-analyses. Inconsistency analyses using the node-splitting method were performed to confirm the results of network meta-analysis. RESULTS: A total of 53 studies with 3037,357 participants were included in the current systematic review. Among these, 16 provided evidence of structural brain abnormalities, and 38 provided evidence of cognitive impairment and dementia. Analysis of evidence of categorical kidney function showed a positive association between kidney dysfunction and cerebral small vessel disease (cSVD) (relative risk (RR) 1.77, 95% confidence interval (CI) 1.40-2.24, I2 = 0.0%), but such results were not found in the analyses of evidence where the kidney function was measured as a continuous variable. Meanwhile, analysis of 28 prior longitudinal studies with 194 compatible sets of data showed that the worse kidney function as categorical variables was related to a greater risk of global brain cognitive disorder (RR 1.28, 95% CI 1.20-1.36, I2 = 82.5%). CONCLUSIONS: In this systematic review and meta-analysis, we found a positive association between CKD and functional brain disorders. However, the relationship between the kidney dysfunction and structural abnormalities in the brain remains controversial. As for the opposite relationship, structural brain abnormalities, especially cerebral microbleeds and silent infarction, but not functional brain abnormalities, are associated with worse renal function. In addition, a higher UACR, but not a lower eGFR, was associated with a higher risk of Alzheimer's disease and vascular dementia.