Obesity Blunts the Effect of Mesenchymal Stem Cell-Derived Extracellular Vesicles.

Introduction: Mesenchymal stem/stromal cell-derived extracellular vesicles (MSC-EVs) are paracrine vectors with therapeutic functions comparable to their parent cells. However, it remains unclear if donor obesity affects their therapeutic functions. We tested the hypothesis that the curative effect of human adipose tissue-derived MSC-EVs (A-MSC-EVs) is blunted by obesity. Methods: MSC-EVs were isolated by ultracentrifugation from mesenchymal stem/stromal cells (MSCs) collected from abdominal subcutaneous fat of obese and lean human subjects (obese and lean-MSC-EVs, respectively) and injected into the aorta of mice 2 weeks after renal artery stenosis (RAS) induction. Magnetic resonance imaging studies were conducted 2 weeks after MSC-EVs delivery to determine renal function. The effect of MSC-EVs on tissue injury was assessed by histology and gene expression of inflammatory factors, including interleukin (IL)-1ß, IL-6, monocyte chemotactic protein-1 (MCP-1), and tumor necrosis factor alpha (TNF-α). Oxidative damage, macrophage infiltration, plasma renin, and hypoxia inducible factor-1α (HIF-1α) were also assessed. Results: Tracking showed that MSC-EVs localized in the kidney tissue, including glomeruli and tubules. All MSC-EVs decreased systolic blood pressure (SBP) and plasma renin and improved the poststenotic kidney (STK) volume, but obese-MSC-EVs were less effective than lean-MSC-EVs in improving medullary hypoxia, fibrosis, and tubular injury. Lean-MSC-EVs decreased inflammation, whereas obesity attenuated this effect. Only lean-MSC-EVs decreased STK cortical HIF-1α expression. Conclusion: Obesity attenuates the antihypoxia, antifibrosis, antiinflammation, and tubular repair functions of human MSC-EVs in chronic ischemic kidney disease. These observations may have implications for the self-repair potency of obese subjects and for the use of autologous MSC-EVs in regenerative medicine.

Autologous Extracellular Vesicles Attenuate Cardiac Injury in Experimental Atherosclerotic Renovascular Disease More Effectively Than Their Parent Mesenchymal Stem/Stromal Cells.

Atherosclerotic renovascular disease (RVD) leads to hypertension, chronic kidney disease (CKD), and heart disease. Intrarenal delivery of mesenchymal stem cells (MSCs) and MSC-derived extracellular vesicles (EVs) attenuate renal injury and suppress release of inflammatory cytokines in porcine RVD. We hypothesized that this strategy would also be useful for cardioprotection. Pigs with renovascular hypertension and metabolic syndrome were studied 4 weeks after treatment with a single intrarenal infusion of autologous MSCs, EVs, or vehicle. Cardiac structure and function were assessed in vivo, and myocardial remodeling and expression of the pro-fibrotic factor growth factor receptor-bound protein-2 (Grb2) were measured ex-vivo. Inflammatory cytokine levels were measured in the systemic circulation and myocardial tissue. Blood pressure was elevated in all RVD groups, but serum creatinine increased in RVD and decreased in both RVD + MSCs and RVD + EVs. RVD-induced diastolic dysfunction (lower E/A ratio) was normalized in both MSCs- and EVs- treated pigs. Intrarenal delivery of MSCs and EVs also attenuated RVD-induced myocardial fibrosis, collagen deposition, and Grb2 expression, yet EVs restored capillary density and inflammation more effectively than MSCs. These observations suggest that autologous EVs attenuate cardiac injury in experimental RVD more effectively than their parent MSCs.

TSG-6 (Tumor Necrosis Factor-α-Stimulated Gene/Protein-6): An Emerging Remedy for Renal Inflammation.

The inflammatory response is a major pathological feature in most kidney diseases and often evokes compensatory mechanisms. Recent evidence suggests that TSG-6 (tumor necrosis factor-α-stimulated gene/protein-6) plays a pivotal role in anti-inflammation in various renal diseases, including immune-mediated and nonimmune-mediated renal diseases. TSG-6 has a diverse repertoire of anti-inflammatory functions: it potentiates antiplasmin activity of IαI (inter-α-inhibitor) by binding to its light chain, crosslinks hyaluronan to promote its binding to cell surface receptor CD44, and thereby regulate the migration and adhesion of lymphocytes, inhibits chemokine-stimulated transendothelial migration of neutrophils by directly interacting with the glycosaminoglycan binding site of CXCL8 (CXC motif chemokine ligand-8), and upregulates COX-2 (cyclooxygenase-2) to produce anti-inflammatory metabolites. Hopefully, further developments can target this anti-inflammatory molecule to the kidney and harness its remedial properties. This review provides an overview of the emerging role of TSG-6 in blunting renal inflammation.

IL-10 partly mediates the ability of MSC-derived extracellular vesicles to attenuate myocardial damage in experimental metabolic renovascular hypertension.

Extracellular vesicles (EVs) obtain properties of immunomodulation and tissue repair from their parental mesenchymal stem cells (MSCs), and upon delivery may be associated with fewer adverse events. EVs derived from adipose-tissue MSCs restored kidney function by attenuating kidney inflammation in a swine model of metabolic syndrome (MetS) and renal artery stenosis via anti-inflammatory pathways. EVs also ameliorated myocardial injury in renovascular hypertension (RVH) secondary to inflammation in cardiorenal disease, but the mechanisms regulating this effect are unknown. We hypothesize that the anti-inflammatory cytokine interleukin (IL)-10 mediates the reparative effects of EVs on cardiovascular complications in a preclinical swine model with coexisting MetS and RVH. Twenty-three pigs established as Lean controls or RVH models were observed for 16 weeks. At 12 weeks RVH subgroups received an intrarenal delivery of 1011 either wildtype (WT) EVs or EVs after IL-10 knockdown (KD) (RVH+WT-EVs or RVH+IL-10-KD-EVs, respectively). Cardiac and renal function were studied in-vivo and myocardial tissue injury in-vitro 4 weeks later. RVH pigs showed myocardial inflammation, fibrosis, and left ventricular diastolic dysfunction. WT-EVs attenuated these impairments, increased capillary density, and decreased myocardial inflammation in-vivo. In-vitro, co-incubation with IL-10-containing WT-EVs decreased activated T-cells proliferation and endothelial cells inflammation and promoted their migration. Contrarily, these cardioprotective effects were largely blunted using IL-10-KD-EVs. Thus, the anti-inflammatory and pro-angiogenic effects of EVs in RVH may be partly attributed to their cargo of anti-inflammatory IL-10. Early intervention of IL-10-containing EVs may be helpful to prevent cardiovascular complications of MetS concurrent with RVH.

Exogenous pericyte delivery protects the mouse kidney from chronic ischemic injury.

Pericytes are considered reparative mesenchymal stem cell-like cells, but their ability to ameliorate chronic ischemic kidney injury is unknown. We hypothesized that pericytes would exhibit renoprotective effects in murine renal artery stenosis (RAS). Porcine kidney-derived pericytes (5 × 105) or vehicle were injected into the carotid artery 2 wk after the induction of unilateral RAS in mice. The stenotic kidney glomerular filtration rate and tissue oxygenation were measured 2 wk later using magnetic resonance imaging. We subsequently compared kidney oxidative stress, inflammation, apoptosis, fibrosis, and systemic levels of oxidative and inflammatory cytokines. Treatment of xenogeneic pericytes ameliorated the RAS-induced loss of perfusion, glomerular filtration rate, and atrophy in stenotic kidneys and restored cortical and medullary oxygenation but did not blunt hypertension. Ex vivo, pericytes injection partially mitigated RAS-induced renal inflammation, fibrosis, oxidative stress, apoptosis, and senescence. Furthermore, coculture with pericytes in vitro protected pig kidney-1 tubular cells from injury. In conclusion, exogenous delivery of renal pericytes protects the poststenotic mouse kidney from ischemic injury, underscoring the therapeutic potential role of pericytes in subjects with ischemic kidney disease.NEW & NOTEWORTHY Our study demonstrates a novel pericyte-based therapy for the injured kidney. The beneficial effect of pericyte delivery appears to be mediated by ameliorating oxidative stress, inflammation, cellular apoptosis, and senescence in the stenotic kidney and improved tissue hypoxia, vascular loss, fibrosis, and tubular atrophy. Our data may form the basis for pericyte-based therapy, and additional research studies are needed to gain further insight into their role in improving renal function.

Chemiluminescence of doped carbon dots with H2O2-KMnO4 system for the detection of Cu2+ and tannin.

The carbon dots doped with chlorine and phosphorus (CDs-Cl,P) were used as chemiluminescence (CL) reagent for the sensitive detection of copper ions (Cu2+) and tannin (TA). The CDs-Cl,P was found to strongly enhance the reaction of H2O2 and KMnO4 in alkaline medium. The enhanced CL behavior of CDs-Cl,P was investigated and it was found that some radicals such as •OH, •O2- and 1O2 appeared in the CL reaction process. The participation of Cu2+ could result in an enhanced CL intensity of the CDs-Cl,P-H2O2-KMnO4 system due to the Cu2+-catalyzed decomposition of H2O2 resulting in more •OH generation. Therefore, the CDs-Cl,P-H2O2-KMnO4 system was used to selectively quantify Cu2+ in solution by CL emission. A linear increase was observed between CL intensity and Cu2+ concentration. The CDs-Cl,P-H2O2-KMnO4 system allowed the detection of Cu2+ down to lower concentration of 0.1 µM with a linear range of 0.2-60.0 µM. Moreover, TA as a common polyphenolic compound, could selectively decrease the CL signal of the CDs-Cl,P-H2O2-KMnO4-Cu2+ system due to its complexation with Cu2+. On this basis, the CL assay for TA was also developed. The detection limit was 0.14 µM and the linear range was from 5.0 µM to 100.0 µM. The proposed method was successfully applied to the determination of Cu2+ and TA in water, rice dumplings leaves, sodium copper chlorophyllin and wine samples with satisfactory results.

Transcriptional profile changes after treatment of ischemia reperfusion injury-induced kidney fibrosis with 18ß-glycyrrhetinic acid.

INTRODUCTION: Chronic kidney disease (CKD) is characterized by renal fibrosis without effective therapy. 18ß-Glycyrrhetinic acid (GA) is reported to have detoxification and anti-inflammatory functions and promotes tissue repair. However, the role of GA in CKD remains unclear. In this study, we investigated whether GA has a potential therapeutic effect in kidney fibrosis. METHODS: A renal fibrosis mouse model was established by ischemia/reperfusion (I/R) injury via clamping unilateral left renal pedicle for 45 min; then, the mice were treated with vehicle or GA. Kidney tissues and blood samples were extracted 14 days after reperfusion and renal function, histopathological staining, quantitative PCR, and western blotting were performed. RNA-seq was performed to explore the changes in the transcriptional profile after GA treatment. RESULTS: Renal function, pathological and molecular analysis displayed that fibrosis was successfully induced in the I/R model. In the GA treatment group, the severity of fibrosis gradually reduced with the best effect seen at a concentration of 25 mg kg -1. A total of 970 differentially expressed genes were identified. Pathway enrichment showed that reduced activation and migration of inflammatory cells and decreased chemokine interaction in significant pathways. Protein-protein interaction networks were constructed and 15 hub genes were selected by degree rank, including chemokines, such as C3, Ccl6, Ccr2, Ptafr, Timp1, and Pf4. CONCLUSIONS: GA may alleviate renal fibrosis by inhibiting the inflammatory response. GA is a promising therapy that may perhaps be used in treating renal fibrosis and CKD.

Znhit1 controls meiotic initiation in male germ cells by coordinating with Stra8 to activate meiotic gene expression.

The switch from mitosis to meiosis ensures the successive formation of gametes. However, it remains unclear how meiotic initiation occurs within the context of chromatin. Recent studies have shown that zinc finger HIT-type containing 1 (Znhit1), a subunit of the SRCAP chromatin remodeling complex, plays essential roles in modulating the chromatin structure. Herein, we report that the germline-conditional deletion of Znhit1 in male mice specifically blocks meiotic initiation. We show that Znhit1 is required for meiotic prophase events, including synapsis, DNA double-strand break formation, and meiotic DNA replication. Mechanistically, Znhit1 controls the histone variant H2A.Z deposition, which facilitates the expression of meiotic genes, such as Meiosin, but not the expression of Stra8. Interestingly, Znhit1 deficiency disrupts the transcription bubbles of meiotic genes. Thus, our findings identify the essential role of Znhit1-dependent H2A.Z deposition in allowing activation of meiotic gene expression, thereby controlling the initiation of meiosis.

Poly(I:C)-Induced Mesenchymal Stem Cells Protect the Kidney Against Ischemia/Reperfusion Injury via the TLR3/PI3K Pathway.

Objective: To investigate the effect and protective mechanism of mesenchymal stem cell subpopulations on acute kidney injury by establishing a mouse model of renal ischemia-reperfusion injury. Methods: Male C57BL/6 mice were randomly divided into five groups, namely, sham-operation group and those treated with normal saline, untreated mesenchymal stem cells, mesenchymal stem cells treated with lipopolysaccharide (LPS, pro-inflammatory phenotype) and mesenchymal stem cells treated with polyinosinic-polycytidylic acid (poly[I:C], anti-inflammatory phenotype) respectively. The renal function, histopathological damage, circulating inflammation levels and antioxidant capacity of mice were evaluated. The PI3 kinase p85 (PI3K) inhibitor was added into the conventional mesenchymal stem cell cultures in vitro to observe its effects on the secretion of anti-inflammatory cytokines. Results: Mesenchymal stem cells treated with poly(I:C) (anti-inflammatory phenotype) could effectively reduce serum creatinine and blood urea nitrogen, attenuate histopathological damage and apoptosis level, decrease the level of circulating pro-inflammatory cytokines and increase the level of circulating anti-inflammatory cytokines, enhance peroxidase activity and reduce malondialdehyde content at each time point. After the addition of the PI3K inhibitor, the mRNA expression and protein secretion of indoleamine 2,3-dioxygenase 1 and heme oxygenase 1 of various mesenchymal stem cells were significantly reduced, and that of mesenchymal stem cells treated with poly(I:C) (anti-inflammatory phenotype) was more obvious. Conclusions: Polyriboinosinic-polyribocytidylic acid (poly[I:C]), a synthetic double-stranded RNA, whose pretreatment induces mesenchymal stem cells to differentiate into the anti-inflammatory phenotype. Anti-inflammatory mesenchymal stem cells induced by poly(I:C) can better protect renal function, alleviate tissue damage, reduce circulating inflammation levels and enhance antioxidant capacity, and achieve stronger anti-inflammatory effects through the TLR3/PI3K pathway.

Highly individual- and tissue-specific expression of glycoprotein group A and B blood antigens in the human kidney and liver.

BACKGROUND: Currently, research on the quantitative distribution of ABO antigens in different organs and tissues remains limited. We aimed to examine the individual characteristics of blood group glycoprotein A and B antigen expression in human kidneys and livers. METHODS: We obtained human samples, including the renal artery, renal vein, renal tissue, hepatic artery, hepatic vein, portal vein, and hepatic tissue, from 24 deceased organ transplant donors. The expression of the blood group antigens glycoprotein A and B was analysed and compared by Western blotting. RESULTS: There was no significant difference in the expression between blood group glycoprotein A and B antigens at any of the seven sites (p > 0.05). The expression of both A and B antigens was highest in renal tissue and the portal vein and was lowest in the renal artery. A large difference in glycoprotein antigen expression was observed among various donors or different regions of the same individual. Univariate analysis revealed that glycoprotein A/B antigens were affected by the age and sex of donors and were significantly higher in males and in young people. CONCLUSIONS: Our study found that blood group glycoprotein antigen expression showed certain trends and distinct distribution in the kidney, liver, and vessels among individuals and in different regions of the same individual, which may explain the different clinical outcomes of patients who received ABO-incompatible transplantation.

Mesenchymal Stem Cell Protects Injured Renal Tubular Epithelial Cells by Regulating mTOR-Mediated Th17/Treg Axis.

The increase in T helper 17 cell (Th17)-mediated pro-inflammatory response and decrease in regulatory T cell (Treg)-mediated anti-inflammatory effect aggravate renal tubular epithelial cell (RTEC) injury. However, increasing evidence indicated that mesenchymal stem cell (MSC) possessed the ability to control the imbalance between Th17 and Treg. Given that Th17 and Treg are derived from a common CD4+ T cell precursor, we summarize the current knowledge of MSC-mediated inhibition of the mammalian target of rapamycin (mTOR), which is a master regulator of CD4+ T cell polarization. During CD4+ T cell differentiation, mTOR signaling mediates Th17 and Treg differentiation via hypoxia-inducible factor-1α (HIF-1α)-dependent metabolic regulation and signaling pathway, as well as mTOR-mediated phosphorylation of signal transducer and activator of transcription (STAT) 3 and 5. Through interfering with mTOR signaling, MSC restrains CD4+ T cell differentiation into Th17, but in turn promotes Treg generation. Thus, this review indicates that MSC-mediated Th17-to-Treg polarization is expected to act as new immunotherapy for kidney injury.

Effect of urea feeding on transforming and migrating soil fluorine in a tea garden of hilly region.

The hilly region of western Sichuan is famous for producing Mengding-mountain tea in China. However, it is very easy to enrich fluorine (F) in tea, which recently raised people's concern on fluorosis. In this study, we simulated the local special climate conditions, especially the natural precipitation through column leaching experiment to investigate the effect of fertilization on F desorption from soil. The results suggested different fertilizers could greatly affect desorption of F from soil, but only urea (CO(NH2)2) could significantly and continuously promote the dissolution of F from soil. Furthermore, to reveal the effect of CO(NH2)2 on migration of F from soil to tea, field plots experiment in a tea garden was carried out. The results showed that CO(NH2)2 promoted soil acidification continuously, resulting in the increase of dissolved F and Al content in soil, which were migrated to tea in the form of F-Al complex. Therefore, the key to reducing the F content in tea is to alleviate soil acidification and reduce F-Al complex content in soil. Most importantly, with CO(NH2)2 addition, the contents of F in tea increased significantly from first bud to fifth bud in comparison with those of without CO(NH2)2, especially in 2016, indicating the accelerating and prolonging enrichment of F in tea by adding CO(NH2)2. This study would have important guidance for controlling F mitigation from soil to tea by managing fertilizers application and anthropogenic activities.

Snai1-induced partial epithelial-mesenchymal transition orchestrates p53-p21-mediated G2/M arrest in the progression of renal fibrosis via NF-κB-mediated inflammation.

Renal fibrosis is the common feature of all progressive kidney diseases and exerts great burden on public health worldwide. The maladaptive repair mechanism of tubular epithelial cells, an important mediator of renal fibrogenesis, manifests with partial epithelial-mesenchymal transition (EMT) and cell cycle arrest. The aim of this study is to investigate the possible correlation between partial EMT and cell cycle arrest, and elucidate the underlying mechanism. We examined human kidney allograft samples with interstitial fibrosis and three mice renal fibrosis models, unilateral ureter obstruction (UUO), ischemia-reperfusion injury, and Adriamycin nephropathy. The partial EMT process and p53-p21 axis were elevated in both human allograft with interstitial fibrosis, as well as three mice renal fibrosis models, and showed a time-dependent increase as fibrosis progressed in the UUO model. Snai1 controlled the partial EMT process, and led to parallel changes in renal fibrosis, G2/M arrest, and inflammation. p53-p21 axis arrested cell cycle at G2/M, and prompted partial EMT and fibrosis together with inflammation. NF-κB inhibitor Bay11-7082 disrupted the reciprocal loop between Snai1-induced partial EMT and p53-p21-mediated G2/M arrest. We demonstrated the reciprocal loop between partial EMT and G2/M arrest of TECs during renal fibrogenesis and revealed NF-κB-mediated inflammatory response as the underlying mechanism. This study suggests that targeting NF-κB might be a plausible therapeutic strategy to disrupt the reciprocal loop between partial EMT and G2/M arrest, therefore alleviating renal fibrosis.

Bioinformatics analysis of pathways of renal infiltrating macrophages in different renal disease models.

BACKGROUND: Recent studies have suggested that macrophages are significantly involved in different renal diseases. However, the role of these renal infiltrating macrophages has not been entirely uncovered. To further clarify the underlying mechanism and identify therapeutic targets, a bioinformatic analysis based on transcriptome profiles was performed. METHODS: Three transcription profiling datasets, GSE27045, GSE51466 and GSE75808, were obtained from the Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) were assessed by Gene Ontology (GO) functional annotation, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and gene set enrichment analysis (GSEA). RESULTS: The classic signaling pathways and metabolic pathways of macrophages infiltrating the kidney in different pathophysiological processes, including lupus nephritis (LN), renal crystal formation and renal ischemia-reperfusion injury (IRI), were analysed. Furthermore, the common classical pathways significantly altered in the three renal disorders were the oxidative phosphorylation, VEGF signaling and JAK/STAT signaling pathways, while the renin-angiotensin system was uniquely altered in LN, the glycolysis and gluconeogenesis pathways were uniquely altered in models of renal crystal formation, and the calcium signaling pathway was specific to renal IRI. CONCLUSIONS: Via bioinformatics analysis, this study revealed the transcriptional features of macrophages in murine LN, renal crystal formation and IRI models, which may serve as promising targets for mechanistic research and the clinical treatment of multiple renal diseases.

Effect of donor kidney morphology parameters on the prognosis in living kidney transplantation recipients.

BACKGROUND: The effect of donor kidney morphology parameters on the prognosis of renal transplant recipients remains unclear. METHODS: We conducted a retrospective cohort study consisting of 290 pairs of donors and recipients who underwent living related renal transplantation in our center between December 2013 and December 2015. The donor kidney morphology parameters, demographic characteristics and renal function of the included participants were collected and analyzed. RESULTS: The univariate linear regression analysis revealed that the donor kidney weight (DKW)/recipient body weight (RBW), DKW/recipient body surface area (RBSA), DKW/recipient body mass index (RBMI), donor kidney volume (DKV)/RBW, DKV/RBSA, DKV/RBMI, and donor body weight (DBW)/RBW were significantly correlated with estimated glomerular filtration rate (eGFR) and serum creatinine in recipients within two years of transplantation. In our multivariate linear regression analysis, DKW/RBW and donor age significantly correlated with eGFR at 6, 12, 18 and 24 months after transplantation. DKW/RBW had the best prediction performance for good renal allograft function at 12 months after transplantation. We found that when the age of the donor was 55 years and above, the prediction performance of the nephron dosing to the recipient's metabolic demands mismatch was elevated. After grouping according to the donor's age and DKW/RBW, the allograft function from different donor ages improved as DKW/RBW increased. The number of recipients who were rejected in the high DKW/RBW group was significantly fewer than those in the low and medium groups the 1, 2, and 3-year graft and patient survival rates were comparable among these groups. Furthermore, we also identified that when the age of the donor was 55 years and above, the threshold of DKW/RBW was 3.09 g/kg via the receiver operating characteristic curve, which predicted a good renal function 12 months after transplantation. CONCLUSIONS: The donor kidney morphology parameters were significantly associated with early renal allograft function, especially when the age of the donor was 55 years and above.

A nitrogen doped carbon dots-enhanced peroxynitrous acid chemiluminescence method for 2-naphthol detection.

A weak CL emission was initiated by peroxynitrous acid (PA) produced by the interaction of nitrite with hydrogen peroxide in sulphuric acid solution. In the presence of nitrogen doped carbon dots (NCDs), the CL intensity was enhanced significantly. The CL mechanism of the NCDs-PA system was studied using the CL spectrum, FL spectrum and the effect of radical scavengers. The NCDs-PA CL system was developed for the determination of 2-naphthol (2-NAP) based on its inhibition effect. The reduced CL intensity was proportional to the concentration of 2-NAP in the range from 0.3 to 20.0 µM and the detection limit was 48.0 nM. This method had been successfully applied to determine 2-NAP in environmental water samples with recoveries of 99.5-102.8%.

Chromatin remodeler Znhit1 preserves hematopoietic stem cell quiescence by determining the accessibility of distal enhancers.

Hematopoietic stem cell (HSC) utilizes its quiescence feature to combat exhaustion for lifetime blood cell supply. To date, how certain chromatin architecture and subsequent transcription profile permit HSC quiescence remains unclear. Here, we show an essential role of chromatin remodeler zinc finger HIT-type containing 1 (Znhit1) in maintaining HSC quiescence. We find that loss of Znhit1 leads to exhaustion of stem cell pool and impairment of hematopoietic function. Mechanically, Znhit1 determines the chromatin accessibility at distal enhancers of HSC quiescence genes, including Pten, Fstl1, and Klf4, for sustained transcription and consequent PI3K-Akt signaling inhibition. Moreover, Znhit1-Pten-PI3K-Akt axis also participates in controlling myeloid expansion and B-lymphoid specification. Our findings therefore identify a dominant role of Znhit1-mediated chromatin remodeling in preserving HSC function for hematopoietic homeostasis.

Thymoglobulin vs. ATG-Fresenius as Induction Therapy in Kidney Transplantation: A Bayesian Network Meta-Analysis of Randomized Controlled Trials.

Background: Thymoglobulin (THG) and antithymocyte globulin-Fresenius (ATG-F) have not been compared directly as induction therapies in kidney transplantation. Materials and Methods: We performed a Bayesian network meta-analysis to compare THG with ATG-F by pooling direct and indirect evidence. Surface under the cumulative ranking curve (SUCRA) values were used to compare the superiority of one method over the other. Results: A total of 27 randomized controlled trials (RCT) were eligible for the network meta-analysis. Efficacy endpoints, as well as safety indicators, were statistically comparable. For efficacy endpoints, THG seemed inferior to ATG-F in preventing delayed graft function [odds ratio (OR): 1.27; SUCRA: 78% vs. 58%], patient deaths (OR: 2.78; SUCRA: 83% vs. 34%), and graft loss (OR: 1.40; SUCRA: 83% vs. 59%), but superior to ATG-F in biopsy-proven acute rejection (BPAR; OR: 0.59; SUCRA: 78% vs. 39%) and steroid-resistant BPAR prevention (OR: 0.61; SUCRA: 76% vs. 49%) within the first year. For safety endpoints, THG was associated with higher risk of infection (OR: 1.49, SUCRA: 79% vs. 54%), cytomegalovirus infection (OR: 1.04; SUCRA: 40% vs. 37%), de novo diabetes (OR: 1.10; SUCRA: 90% vs. 30%), and malignancy (OR: 8.40; SUCRA: 89% vs. 6%) compared to ATG-F. A subgroup analysis of patients at high risk for immunologic complications revealed similar results, but THG performed better for graft loss (OR: 0.82; SUCRA: 68% vs. 54%). Conclusion: ATG-F seemed to be more effective than THG in improving the short-term kidney transplantation outcomes. Prospective head-to-head comparison of THG and ATG-F with larger sample sizes and longer follow-up is still required.

Non-linear Relationship between Tacrolimus Blood Concentration and Acute Rejection After Kidney Transplantation: A Systematic Review and Dose-Response Meta-Analysis of Cohort Studies.

BACKGROUND: Maintaining the exposure of tacrolimus (Tac) after kidney transplantation (KT) must be necessary to prevent acute rejection (AR) and improve graft survival，but there is still no clear consensus on the optimal Tac target blood concentration and concentration-effect relationship is poorly defined. METHODS: We conducted a dose-response meta-analysis to quantitatively assess the association between Tac blood concentration and (AR) or adverse effects after KT. A comprehensive search of PubMed, Embase and Cochrane library databases was conducted to find eligible studies up to 10th September 2018. Unpublished data from patients receiving KT in West China Hospital (Sichuan University, China) were also collected. Both twostage dose-response and one-stage dose-response meta-analysis models were used to improve the statistical power. RESULTS: A total of 4967 individuals from 10 original studies and 1453 individuals from West China Hospital were eligible for the ultimate analysis. In the two-stage dose-response meta-analysis model, we observed a significant non-linear relationship between Tac blood concentration and AR (P < 0.001) with moderate heterogeneity (I2 = 46.0%, P = 0.08). Tac blood concentration at 8ng/ml was associated with the lowest risk of AR (RR: 0.26, 95%CI: 0.13 - 0.54) by reference to 2ng/ml. Tac concentration at 7.0 - 11.0 ng/ml reduced the risk of AR by at least 70%, 5-14 ng/ml by at least 60%, and 4.5 - 14 ng/ml at least 50%. In the one-stage dose-response model, we also found a strong non-linear relationship between Tac and AR (P < 0.001) with moderate heterogeneity (I2 = 41.2%, P = 0.10). Tac concentration of 7.5 ng/ml was associated with the lowest risk of AR (RR: 0.35, 95%CI: 0.16 - 0.77). The blood concentration at 5.5 - 9.5 ng/ml was associated with the reduced AR by at least 60% and 4.5 - 10.5 ng/ml by at least 50% by reference to 2 ng/ml. CONCLUSION: Maintaining Tac blood concentration at 5 - 9.5 ng/ml within the first year may prevent AR most effectively.

Tacrolimus Trough Level at the First Month May Predict Renal Transplantation Outcomes Among Living Chinese Kidney Transplant Patients: A Propensity Score-Matched Analysis.

BACKGROUND: Monitoring and maintaining a stable tacrolimus trough level is essential because of its narrow therapeutic window and considerable fluctuation in the early phase after kidney transplantation. However, optimal tacrolimus exposure early after transplantation remains unclear among Chinese patients. METHODS: In this propensity score-matched cohort study, we thoroughly investigated the association between tacrolimus trough level at the first month and acute rejection (AR) as well as infection within the first year after kidney transplantation. RESULTS: In a first step, a total of 1415 patients were divided into 3 groups according to the receiver operating characteristic curve: low-level group (410 patients with a tacrolimus trough level <5.35 ng/mL at the first month), median-level group (466 patients with a tacrolimus trough level from 5.35 to 7.15 ng/mL), and high-level group (539 patients with a tacrolimus trough level >7.15 ng/mL). Ultimately, 363 and 459 pairs of cases were enrolled by using 2 propensity score matches between low- and median-level groups and between high- and median-level groups, respectively. Compared with patients in the low-level group, patients in the median-level group had lower risk of AR without increased incidence of infection (AR, 12.4% versus 5.7%, P = 0.02; infection, 13.2% versus 13.2%, P = 1.00 for low- and median-level groups, respectively) within the first year. Compared with patients in the high-level group, patients in the median-level group had lower incidence of infection without the growing risk of AR (infection, 17.6% versus 12.2%, P = 0.021; AR, 4.6% versus 5.4%, P = 0.545 for high- and median-level groups, respectively) within the first year. Multilogistic analysis showed that tacrolimus trough levels were an independent factor for AR (odds ratio, 0.749, 95% confidence interval, 0.632-0.888, P = 0.001). Tacrolimus trough levels were also associated with infection (odds ratio 1.110, 95% confidence interval, 1.013-1.218, P = 0.001). Serum creatinine levels were similar among groups. No difference was found in 1-, 3-, and 5-year graft survival and patient survival among groups. CONCLUSIONS: The tacrolimus trough level maintained between 5.35 and 7.15 ng/mL at the first posttransplant month may prevent AR without increasing the incidence of infection within the first year after living kidney transplantation among Chinese patients.