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Background Renal hypoxia and ischemia significantly contribute to chronic kidney disease (CKD) progression, underscoring the need for noninvasive quantitative assessments. This study employs blood oxygenation level-dependent magnetic resonance imaging (BOLD-MRI) and arterial spin labeling (ASL) MRI to comprehensively evaluate renal oxygenation and blood flow in CKD patients.Methods Forty-two CKD patients across stages 1–5 and ten healthy volunteers underwent simultaneous BOLD-MRI and ASL-MRI. We measured oxygenation (T2* values) and renal blood flow (RBF) in both the renal cortex and medulla, assessing their correlations with estimated glomerular filtration rate (eGFR) and other renal function indicators.Results BOLD and ASL revealed higher oxygenation and RBF in the renal cortex than in the medulla. Across CKD stages 2–5, both cortical and medullary oxygenation levels, as well as RBF, were lower than those in the control group and progressively decreased with CKD advancement. Additionally, renal oxygenation and blood flow levels positively correlated with serum creatinine (SCr), cystatin C (Cys C), and blood urea nitrogen (BUN), and negatively correlated with estimated glomerular filtration rate (eGFR) (p 0.05). Notably, patients with CKD stages 1–3 exhibited strong correlations between renal oxygenation levels, RBF, and eGFR, while those with CKD stages 4–5 displayed weak correlations.Conclusion BOLD-MRI and ASL-MRI effectively measure renal oxygenation and perfusion noninvasively, confirming their utility in tracking CKD progression. These modalities provide accurate assessments of renal function and hypoxic-ischemic injuries across CKD stages, particularly in the early stages.

Objective Shenkang injection (SKI) has been widely used in China for many years for the treatment of kidney disease. The objective of this systematic review was to assess the efficacy of Shenkang injection for the treatment of acute kidney injury (AKI).Methods A search was conducted across seven databases, encompassing data from the inception of each database through October 8th, 2023. Randomized controlled trials comparing SKI-treated AKI patients with control subjects were extracted. The main outcome measure was serum creatinine (SCr) levels. Secondary outcomes included blood urea nitrogen (BUN), serum cystatin C (CysC), 24-h urine protein (24 h-Upro) levels, APACHE II score and adverse reactions.Results This meta-analysis included eleven studies, and the analysis indicated that, compared with the control group, SKI significantly decreased SCr [WMD = −23.31, 95% CI (-28.06, −18.57); p

Background Renal hypoxia plays a key role in the progression of chronic kidney disease (CKD). Shen Shuai II Recipe (SSR) has shown good results in the treatment of CKD as a common herbal formula. This study aimed to explore the effect of SSR on renal hypoxia and injury in CKD rats.Methods Twenty-five Wistar rats underwent 5/6 renal ablation/infarction (A/I) surgery were randomly divided into three groups: 5/6 (A/I), 5/6 (A/I) + losartan (LOS), and 5/6 (A/I) + SSR groups. Another eight normal rats were used as the Sham group. After 8-week corresponding interventions, blood oxygenation level-dependent functional magnetic resonance imaging (BOLD-fMRI) was performed to evaluate renal oxygenation in all rats, and biochemical indicators were used to measure kidney and liver function, hemoglobin, and proteinuria. The expression of fibrosis and hypoxia-related proteins was analyzed using immunoblotting examination.Results Renal oxygenation, evaluated by BOLD-fMRI as cortical and medullary T2* values (COT2* and MET2*), was decreased in 5/6 (A/I) rats, but increased after SSR treatment. SSR also downregulated the expression of hypoxia-inducible factor-1α (HIF-1α) in 5/6 (A/I) kidneys. With the improvement of renal hypoxia, renal function and fibrosis were improved in 5/6 (A/I) rats, accompanied by reduced proteinuria. Furthermore, the COT2* and MET2* were significantly positively correlated with the levels of creatinine clearance rate (Ccr) and hemoglobin, but negatively associated with the levels of serum creatinine (SCr), blood urea nitrogen (BUN), serum cystatin C (CysC), serum uric acid (UA), 24-h urinary protein (24-h Upr), and urinary albumin:creatinine ratio (UACR).Conclusion The degree of renal oxygenation reduction is correlated with the severity of renal injury in CKD. SSR can improve renal hypoxia to attenuate renal injury in 5/6 (A/I) rats of CKD.

BackgroundProtein Energy Wasting (PEW) has high incidence in adult hemodialysis patients and refers to a state of decreased protein and energy substance. It has been demonstrated that PEW highly affects the quality of survival and increases the risk of death. Nevertheless, its diagnostic criteria are complex in clinic. To simplify the diagnosis method of PEW in adult hemodialysis patients, we previously established a novel clinical prediction model that was well-validated internally using bootstrapping. In this multicenter cross-sectional study, we aimed to externally validate this nomogram in a new cohort of adult hemodialysis patients.MethodsThe novel prediction model was built by combining four independent variables with part of the International Society of Renal Nutrition and Metabolism (ISRNM) diagnostic criteria including albumin, total cholesterol, and body mass index (BMI). We evaluated the performance of the new model using discrimination (Concordance Index), calibration plots, and Clinical Impact Curve to assess its predictive utility.ResultsFrom September 1st, 2022 to August 31st, 2023, 1,158 patients were screened in five medical centers in Shanghai. 622 (53.7%) hemodialysis patients were included for analysis. The PEW predictive model was acceptable discrimination with the area under the curve of 0.777 (95% CI 0.741–0.814). Additionally, the model revealed well-fitted calibration curves. The McNemar test showed the novel model had similar diagnostic efficacy with the gold standard diagnostic method (p > 0.05).ConclusionOur results from this cross-sectional external validation study further demonstrate that the novel model is a valid tool to identify PEW in adult hemodialysis patients effectively.

AbstractContext Salvianolic acid B (SAB) can alleviate renal fibrosis and improve the renal function.Objective To investigate the effect of SAB on renal tubulointerstitial fibrosis and explore its underlying mechanisms.Materials and methods Male C57 mice were subjected to unilateral ureteric obstruction (UUO) and aristolochic acid nephropathy (AAN) for renal fibrosis indication. Vehicle or SAB (10 mg/kg/d, i.p.) were given consecutively for 2 weeks in UUO mice while 4 weeks in AAN mice. The serum creatinine (Scr) and blood urine nitrogen (BUN) were measured. Masson’s trichrome staining and the fibrotic markers (FN and α-SMA) were used to evaluate renal fibrosis. NRK-49F cells exposed to 2.5 ng/mL TGF-β were treated with SAB in the presence or absence of 20 μM 3-DZNep, an inhibitor of EZH2. The protein expression of EZH2, H3k27me3 and PTEN/Akt signaling pathway in renal tissue and NRK-49F cells were measured by Western blots.Results SAB significantly improved the levels of Scr by 24.3% and BUN by 35.7% in AAN mice. SAB reduced renal interstitial collagen deposition by 34.7% in UUO mice and 72.8% in AAN mice. Both in vivo and in vitro studies demonstrated that SAB suppressed the expression of FN and α-SMA, increased PTEN and decreased the phosphorylation of Akt, which were correlated with the down-regulation of EZH2 and H3k27me3. The inhibition of EZH2 attenuated the anti-fibrotic effects of SAB in NRK-49Fs.Conclusion SAB might have therapeutic potential on renal fibrosis of CKD through inhibiting EZH2, which encourages further clinical trials.

This study aims to explore the relationships between renal function, hypoxia, and oxidative stress in chronic kidney disease (CKD). Seventy-six non-dialysis patients with CKD stages 1-5 and eight healthy subjects were included in the clinical research. They were divided into three groups: healthy subjects, CKD stages 1-3, and CKD stages 4-5. In the animal study, 16 rat models of CKD were established through 5/6 renal ablation/infarction (A/I) surgery, and 8 normal rats were split into 3 groups: Sham, CKD, and losartan groups. Blood oxygenation level-dependent magnetic resonance imaging (BOLD-MRI) was used to measure cortical and medullary T2* values (COT2* and MET2*) in all subjects and rats to evaluate renal oxygenation. Biochemical indicators were used to assess renal function and antioxidant capacity. Furthermore, the effects of losartan on renal fibrosis, hypoxia, and oxidative stress were examined using immunoblotting, colorimetric, and fluorometric assays. The results demonstrated significant positive associations between COT2* and MET2* with estimated glomerular filtration rate (eGFR). Patients with CKD stages 4-5 showed significantly lower serum superoxide dismutase (SOD) levels, which also had positive correlations with eGFR, COT2*, and MET2*. Furthermore, losartan treatment resulted in improved renal function and fibrosis, leading to increased levels of COT2*, MET2*, and SOD levels in 5/6 A/I rats. This was accompanied by reduced levels of hypoxia-inducible factor-1 alpha (HIF-1α) and malondialdehyde. Furthermore, losartan restored the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), and suppressed the expression of Kelch-like ECH-associated protein 1 (Keap1) in 5/6 A/I kidneys. The study indicates that decline in renal oxygenation and antioxidant capacity is associated with the severity of renal failure in CKD. Losartan can potentially alleviate renal hypoxia and oxidative stress in the treatment of CKD via Keap1-Nrf2/HO-1 pathway.

Abstract Background Renal tubulointerstitial fibrosis is the hallmark of various chronic kidney diseases. Symmetric dimethylarginine (SDMA) is an independent cardiovascular risk factor in patients with chronic kidney diseases, which is mostly excreted through renal tubules. However, the effect of SDMA on kidneys in a pathological condition is currently unknown. In this study, we investigated the role of SDMA in renal tubulointerstitial fibrosis and explored its underlying mechanisms. Methods Mouse unilateral ureteral obstruction (UUO) and unilateral ischemia–reperfusion injury (UIRI) models were established to study renal tubulointerstitial fibrosis. SDMA was injected into kidneys through ureter retrogradely. TGF-β stimulated human renal epithelial (HK2) cells were used as an in vitro model and treated with SDMA. Signal transducer and activator of transcription-4 (STAT4) was inhibited by berbamine dihydrochloride or siRNA or overexpressed by plasmids in vitro. Masson staining and Western blotting were performed to evaluate renal fibrosis. Quantitative PCR was performed to validate findings derived from RNA sequencing analysis. Results We observed that SDMA (from 0.01 to 10 µM) dose-dependently inhibited the expression of pro-fibrotic markers in TGF-β stimulated HK2 cells. Intrarenal administration of SDMA (2.5 µmol/kg or 25 µmol/kg) dose-dependently attenuated renal fibrosis in UUO kidneys. A significant increase in SDMA concentration (from 19.5 to 117.7 nmol/g, p

AbstractBackground Chronic kidney disease-associated pruritus (CKD-aP) is very common and sometimes refractory to treatment in hemodialysis patients. In a trial conducted in Japan, nalfurafine, effectively reduced itching of treatment-resistant CKD-aP. Our present bridging study aimed to evaluate the efficacy and safety of nalfurafine in Chinese cohort with refractory CKD-aP.Methods In this phase III, multicenter bridging study conducted at 22 sites in China, 141 Chinese cases with refractory CKD-aP were randomly (2:2:1) assigned to receive 5 μg, 2.5 μg of nalfurafine or a placebo orally for 14 days in a double-blind manner. The primary end point was the mean decrease in the mean visual analogue scale (VAS) from baseline.Results A total of 141 patients were included. The primary endpoint analysis based on full analysis set (FAS), the difference of mean VAS decrease between 5 μg nalfurafine and placebo group was 11.37 mm (p = .041); the difference of mean VAS decrease between 2.5 μg and placebo group was 8.81 mm (p = .110). Both differences were greater than 4.13 mm, which met its predefined success criterion of at least 50% efficacy of the key Japanese clinical trial. The per protocol set (PPS) analysis got similar results. The incidence of adverse drug reactions (ADRs) was 49.1% in 5μg, 38.6% in 2.5 μg and 33.3% in placebo group. The most common ADR was insomnia, seen in 21 of the 114 nalfurafine patients.Conclusions Oral nalfurafine effectively reduced itching with few significant ADRs in Chinese hemodialysis patients with refractory pruritus.

Background and Aims: Fibrolamellar carcinoma (FLC) is a rare, difficult-to-treat liver cancer primarily affecting pediatric and adolescent patients, and for which precision medicine approaches have historically not been possible. The DNAJB1-PRKACA gene fusion was identified as a driver of FLC pathogenesis. We aimed to assess whether FLC tumors maintain dependency on this gene fusion and determine if PRKACA is a viable therapeutic target. Methods: FLC patient-derived xenograft (PDX) shRNA cell lines were implanted subcutaneously into female NOD-SCID mice and tumors were allowed to develop prior to randomization to doxycycline (to induce knockdown) or control groups. Tumor development was assessed every 2 days. To assess the effect of treatment with novel selective PRKACA small molecule kinase inhibitors, BLU0588 and BLU2864, FLC PDX tumor cells were implanted subcutaneously into NOD-SCID mice and tumors allowed to develop. Mice were randomized to treatment (BLU0588 and BLU2864, orally, once daily) or control groups and tumor size determined as previously. Results: Knockdown of DNAJB1-PRKACA reversed a FLC-specific gene signature and reduced PDX tumor growth in mice compared to the control group. Furthermore, FLC PDX tumor growth was significantly reduced with BLU0588 and BLU2864 treatment vs control (P = .003 and P = .0005, respectively). Conclusion: We demonstrated, using an inducible knockdown and small molecule approaches, that FLC PDX tumors were dependent upon DNAJB1-PRKACA fusion activity. In addition, this study serves as a proof-of-concept that PRKACA is a viable therapeutic target for FLC and warrants further investigation.

AbstractPurpose Existed methods like biochemical markers improve the accuracy of fluid evaluation for the maintenance hemodialysis patients, but none of them has become the gold standard. This study aimed to evaluate the potential of lung ultrasonography as a useful tool for monitoring the volume status of the patients.Methods A total of 88 patients undergoing maintenance hemodialytic were enrolled in this prospective observational study. Patients were divided into three groups: overhydration (OH), normohydration, and hypohydration according to bioimpedance spectroscopy. Lung ultrasonography parameters, echocardiography parameters, and clinical characteristics of three groups were analyzed. After an average follow-up of 433 days, all-cause mortality among groups was compared.Results The total number of lung comets was statistically reduced in patients after dialysis (Z= −6.891, p

Context Diabetic kidney disease (DKD) is a devastating complication of diabetes. Renal functional deterioration caused by tubular injury is the primary change associated with this disease. Calycosin shows protective roles in various diseases.Objectives This study explored the function and underlying mechanism of calycosin in DKD.Materials and methods HK-2 cells were treated with 25 mM high glucose (HG) to establish a renal tubule injury cell model. Then, the viability of cells treated with 0, 5, 10, 20, 40 and 80 μM of calycosin was measured using Cell Counting Kit-8. For the in vivo model, db/db mice were treated with 10 and 20 mg/kg/day of calycosin; db/m mice served as controls. The histomorphology was analyzed via haematoxylin and eosin staining.Results HG-induced decreased expression of glutathione (491.57 ± 33.56 to 122.6 ± 9.78 μmol/mL) and glutathione peroxidase 4 (inhibition rate 92.3%) and increased expression of lactate dehydrogenase (3.85 ± 0.89 to 16.84 ± 2.18 U/mL), malondialdehyde (3.72 ± 0.66 to 18.2 ± 1.58 nmol/mL), lipid ROS (4.31-fold increase) and NCOA4 (7.69-fold increase). The effects induced by HG could be blocked by calycosin. Moreover, calycosin alleviated the HG-induced decrease of cell viability and the increase of lipid ROS, but erastin could block the effects caused by calycosin. The in vivo model showed that calycosin alleviated the renal injury caused by diabetes.Discussion and conclusion Calycosin has a protective effect on diabetic kidney disease; ferroptosis may be involved in this process.

Abstract Background We aim to study the clinical effect of moxibustion at Laogong interval with Panax notoginseng on the short-term maturation and long-term patency of arteriovenous fistula. Methods Seventy-four pre-dialysis uremic patients who received distal forearm radial-cephalic fistula creations were enrolled in this study and randomly assigned to the control group and experimental group. After arteriovenous fistula creations, the control group underwent handgrip exercise, and the experimental group received moxibustion at Laogong acupoint interval with Panax notoginseng. Both groups received a 12-week treatment and were followed up for 24 weeks in all at the following time points: before creations and 2, 4, 8, 12, 24 weeks after creations. The diameter of anastomosis, the diameter and outflow of draining-veins 5 cm above anastomosis, the diameter and outflow of brachial arteries evaluated the maturation and patency of arteriovenous fistula. Enzyme linked immunosorbent assay determined serum levels of endothelin and nitric oxide. Results The maturity rate in the experimental group was significantly higher than that in the control group at 4 weeks after arteriovenous fistula creations (P = 0.048). The diameter of anastomosis, the diameter of draining veins, and the blood flow of draining veins increased in both groups during the whole 24 weeks. The diameter and blood flow of brachial arteries ascended in both groups during the previous 12 weeks. Compared with the control group, moxibustion at Laogong interval with Panax notoginseng significantly improved the value of the diameter of draining-veins (P = 0.016), the blood flow of draining-veins (P = 0.015), the diameter of brachial arteries (P

Abstract Background Tanshinone I (Tan-I), an ingredient of Salvia miltiorrhiza, displays protective effects in several disease models. We aim to study the effect of Tan-I on renal fibrosis and explore its underlining mechanism. Methods Rat renal fibroblasts (NRK-49F) were used as an in vitro model to study the effect of Tan-I. Mouse renal fibrosis model was induced by unilateral ureteral obstruction (UUO) or peritoneally injection of aristolochic acid I (AAI). Results We found that Tan-I dose-dependently inhibited the expression of pro-fibrotic markers in rat renal fibroblasts. Masson staining and Western blotting analysis showed that Tan-I treatment attenuated renal fibrosis in UUO or AAI induced fibrotic kidneys. RNA sequencing analysis identified inhibin beta-A (INHBA), a ligand of TGF-β superfamily, as a downstream target of Tan-I in fibrotic kidneys, which were further verified by qPCR. Western blotting analysis showed that INHBA is up-regulated in UUO or AAI induced fibrotic kidneys and Tan-I reduced the expression of INHBA in fibrotic kidneys. Inhibition of INHBA by Tan-I was further confirmed in rat fibroblasts. Moreover, knockdown of INHBA reduced the expression of pro-fibrotic markers and abolished the ani-fibrotic effect of Tan-I in rat renal fibroblasts. Conclusions We conclude that Tan-I attenuates fibrosis in fibrotic kidneys through inhibition of INHBA.

With the development of the Internet today, earth shaking changes have taken place compared with the traditional network.In today's network reform, ＆quot;cloud＆quot; has become the mainstream direction of the evolution of enterprise IT architecture, so the requirements for cloud security are becoming higher and higher.The practical deployment scheme of SASE cloud security architecture was introduced to solve the problem of cloud security for customers.A unique and complete SASE solution was proposed, which combined security functions with SD-WAN functions, and realized real-time monitoring, intelligent analysis and automatic interception of malware or malicious activities by building a unified management and control platform and centralized deployment of core security resource pool.Practice has proved that the scheme achieves the expected results in unified management and control, intrusion detection and defense, fine access control and so on, and can fully ensure the cloud security of enterprises.

Introduction: Chronic hypoxia is prevalent in chronic kidney disease (CKD), and Blood oxygenation level-dependent magnetic resonance imaging (BOLD-MRI) provides noninvasive evaluation of renal oxygenation. This study aimed to explore the correlation of renal oxygenation evaluated by BOLD-MRI with renal function. Methods: 97 non-dialysis patients with CKD stages 1-5 and healthy volunteers (HVs) were recruited in the study. Based on their estimated glomerular filtration rate (eGFR), the patients were divided into two groups: CKD stages 1-3 (CKD 1-3) and CKD stages 4-5 (CKD 4-5) . We measured cortical and medullary T2* (COT2* and MET2*) values in all participants by BOLD-MRI. Physiological indices were also recorded and compared among three groups. Correlation of T2* values with clinical characteristics were determined. Results: The COT2* values were significantly higher than MET2* values in all participants. The COT2* and MET2* values of three groups were ranked as HV> CKD 1-3> CKD 4-5 (p 0.4, p 0.05). Urinary microprotein, including urinary alpha1-microglobulin (α1-MG), urinary beta2-microglobulin (β2-MG), and urinary retinol binding protein (RBP), was showed strong correlation with COT2* and MET2* values. According to analysis of receiver-operating characteristic (ROC) curve, we obtained the optimal cut-point between HV and CKD 1-3 were “< 61.17 ms” (sensitivity: 91.23%, specificity: 100%) for COT2* values and “< 35.00 ms” (sensitivity: 77.19%, specificity: 100%) for MET2* values, whereas COT2* values (“< 47.34 ms”; sensitivity: 90.00%, specificity: 92.98%) and MET2* values (“< 25.09 ms”; sensitivity: 97.50%, specificity: 80.70%) between CKD 1-3 and CKD 4-5. Conclusion: The decline of renal oxygenation reflected on T2* values, especially in cortex, may be an effective diagnostic-marker for early detection of CKD.

Border Gateway Protocol (BGP) is the de facto inter-domain routing protocol of today’s global internet for exchanging routing information.However, it was supposed that all participants were reliable without generating routing security issues by mistakes or on purpose when BGP was designed 50 years ago.As Internet is getting involved in all aspects of our society, internet routing security is becoming the problems that couldn’t be ignored anymore.A general architecture was proposed which coved inference of BGP routing knowledge database and provided visibility of global internet routing.Detection of route security events such as routing hijacks and routing leaks were realized.The deployment shows that the system can provide good visibility of internet routing and precise detection of routing security events.

Mammalian protein arginine methyltransferase 3 (PRMT3) catalyzes the monomethylation and dimethylation of the arginine residues of proteins. The role of PRMT3 in renal fibrosis is currently unknown. We aimed to study the role of PRMT3 in renal fibrosis and explored its underlying mechanisms. Quantitative PCR analysis and Western blotting analysis showed that the expression of PRMT3 was up-regulated in unilateral ureteral obstruction (UUO) mouse kidneys. Knockout of Prmt3 gene enhanced interstitial fibrosis in UUO kidneys as shown by Masson staining and Western blotting analysis the expression of pro-fibrotic markers. The production of asymmetric dimethylarginine (ADMA) was increased in wide type UUO kidneys but not further increased in Prmt3 knockout UUO kidneys. Administration of exogeneous ADMA in UUO kidneys blocked the enhanced renal interstitial fibrosis in Prmt3 mutant mice. Moreover, genetic deletion of Prmt3 gene increased blood urea nitrogen levels and renal deposition of collagen in folic acid injected mice. We conclude that PRMT3 inhibits renal tubulointerstitial fibrosis through elevating renal ADMA levels.

Background: Salvianolic acid C (SAC) is a natural compound derived from Salvia miltiorrhiza that can protect against renal diseases. The aims of this work were to explore the effect of SAC on kidney tubulointerstitial fibrosis and study the associated mechanism. Methods: Models for unilateral ureteral obstruction (UUO) and aristolochic acid I (AAI) were established in mice to study renal tubulointerstitial fibrosis. Rat kidney fibroblasts (NRK-49F) and human kidney epithelial cells (HK2) were used as cellular models to evaluate the effects of SAC on kidney fibrosis. Results: Treatment with SAC for two weeks reduced the level of renal tubulointerstitial fibrosis in UUO- and AAI-induced fibrotic kidneys, as demonstrated by Masson’s staining and Western blot. SAC inhibited extracellular matrix protein expression in NRK-49F cells and TGF-β-stimulated HK2 cells in dose-dependent fashion. Moreover, SAC inhibited the expression of epithelial-mesenchymal transition (EMT) factors in animal and cellular models of kidney fibrosis, as well as the EMT-related transcription factor snail. Furthermore, SAC inhibited the fibrosis-related signaling pathway Smad3 in the fibrotic kidneys of two mouse models and in renal cells. Conclusions: We conclude that SAC inhibits EMT and ameliorates tubulointerstitial fibrosis through involvement of the signaling pathway for transforming growth factor-β (TGF-β)/Smad.

Chronic kidney disease (CKD) is a worldwide public health problem that is caused by repeated injuries to the glomerulus or renal tubules. Renal fibrosis commonly accompanies CKD, and it is histologically characterized by excessive deposition of extracellular matrix proteins, such as fibronectin and collagen I, in interstitial areas. Indirect in vivo experimental data suggest that renal asymmetric dimethylarginine (ADMA) exerts antifibrotic activity in CKD. In this study, we aimed to demonstrate that renal ADMA has a direct effect on fibrosis in vivo. Normal saline, ADMA, nonsense control siRNA, Ddah1 siRNA or Ddah2 siRNA was administered into the kidney through the left ureter in a mouse model of unilateral ureteral obstruction (UUO). UUO kidneys were harvested at day 1 or 7. Western blotting was performed to assess the expression of ADMA, DDAH1 and DDAH2 and the expression of fibrotic markers, such as fibronectin, collagen I, α‐smooth muscle actin, phosphorylation of Smad3 and connective tissue growth factor. Masson’s trichrome staining was used to further evaluate renal fibrosis. We observed that intrarenal administration of ADMA increased the renal accumulation of ADMA and attenuated renal fibrosis at days 1 and 7. Knockdown of Ddah1 or Ddah2 increased the amount of ADMA in UUO kidneys and inhibited the expression of fibrotic proteins at days 1 and 7, which was further confirmed by Masson’s staining. Thus, our in vivo data suggest that renal ADMA exerts direct antifibrotic effects in a mouse model of UUO.

The clinical and experimental study into the effects of Chinese herbal medicines on chronic kidney disease has evolved over the past 40 years with new insight into their mechanism and evidence of their clinical effects. Among the many traditional Chinese herbs examined in chronic renal disease, five were found to have evidence of sufficient clinical efficacy, high frequency of use, and well-studied mechanism. They are: Abelmoschus manihot and Huangkui capsule, Salvia miltiorrhiza and its components (tanshinone II A, salvianolic acid A and B); Rhizoma coptidis and its monomer berberine; Tripterygium wilfordii and its components (triptolide, tripterygium glycosides); Kudzu root Pueraria and its monomer Puerarin. These Chinese herbal medications have pharmaceutical effects against fibrosis, inflammation and oxidative stress and also promote renal repair and regeneration. This article reviews their clinical efficacy, anti-fibrotic effects in animal models, and molecular mechanism of action.

Aim: Kidney impairment is observed in patients with COVID-19. The effect of anti-COVID-19 agent remdesivir on kidneys is currently unknown. We aimed to determine the effect of remdesivir on renal fibrosis and its downstream mechanisms.Methods: Remdesivir and its active nucleoside metabolite GS-441524 were used to treat TGF-β stimulated renal fibroblasts (NRK-49F) and human renal epithelial (HK2) cells. Vehicle or remdesivir were given by intraperitoneal injection or renal injection through the left ureter in unilateral ureteral obstruction (UUO) mice. Serum and kidneys were harvested. The concentrations of remdesivir and GS-441524 were measured using LC-MS/MS. Renal and liver function were assessed. Renal fibrosis was evaluated by Masson’s trichrome staining and Western blotting.Results: Remdesivir and GS-441524 inhibited the expression of fibrotic markers (fibronectin and aSMA) in NRK-49F and HK2 cells. Intraperitoneal injection or renal injection of remdesivir attenuated renal fibrosis in UUO kidneys. Renal and liver function were unchanged in remdesivir treated UUO mice. Two remdesivir metabolites were detected after injection. Phosphorylation of Smad3 that was enhanced in cell and animal models for renal fibrosis was attenuated by remdesivir. In addition, the expression of Smad7, an anti-fibrotic factor, was increased after remdesivir treatment in vitro and in vivo. Moreover, knockdown of Smad7 blocked the antifibrotic effect of GS and RDV on renal cells.Conclusion: Remdesivir inhibits renal fibrosis in obstructed kidneys.

Introduction STAT4 is a transcriptional regulator that has been reported to have oncogenic activities in various cancers. In our study, the posttranscriptional regulatory effect of miR-200a-3p on STAT4 and the prognostic significance of miR-200a-3p and STAT4 were evaluated in bladder cancer (BCa). Material and methods Proliferation and apoptosis of BCa cell lines were monitored using CCK-8 and Annexin V-FITC assays, respectively. Gene and protein expression levels in BCa tissues and cells were detected using RT-qPCR and western blotting, respectively. Results Significant downregulation of miR-200a-3p and upregulation of STAT4 were observed in BCa tissues and cells compared with the corresponding non-tumor adjacent tissues. Both STAT4 and miR-200a-3p were validated as independent prognostic indicators in sixty-nine BCa patients for predicting overall survival and disease-free survival. In vitro experimental analyses revealed that knockdown of STAT4 repressed BCa cell growth and elevated cell apoptosis. Molecular interactive analysis revealed STAT4 as a direct target of miR-200a-3p, which could suppress STAT4 protein expression by posttranscriptional repression. Cotransfection of miR-200a-3p mimics and STAT4 overexpression plasmids into BCa cells demonstrated that the antineoplastic activities of miR-200a-3p in vitro were neutralized by overexpressed STAT4. Conclusions The miR-200a-3p/STAT4 signaling cascade plays an important role in the progression of BCa, which provides a new promising target for targeted BCa therapies.

Abstract Background Persistent left superior vena cava (PLSVC) is a common vena cava malformation, and drains blood into the right atrium via the dilated coronary sinus in most cases. It is usually asymptomatic and detected incidentally during invasive procedures or imaging. Whether the hemodialysis catheters can be placed in PLSVC is still controversial now (Stylianou et al. Hemodial Int 11:42-45, 2007). Case presentation Here we report a rare case of catheterization through PLSVC in an end-stage renal disease (ESRD) male patient whose PLSVC connected with pulmonary vein with insufficient blood flow eventually. Among the other 28 cases included in the literature review, 16 cases were non-tunneled catheter and 12 cases were cuffed, tunneled catheter and most of them could provide adequate blood flow. Conclusion PLSVC is a rare malformation and mostly asymptotic, we believe that PLSVC drains blood into the right atrium with enough inner diameter and blood flow can serve as an alternative site for conventional dialysis access. However, the feasibility of hemodialysis catheterization through it and measures to avoid serious complications are still needed to be discussed.

Abstract Background Magnesium lithospermate B (MLB) can promote renal microcirculation. The aim of the current project was to study whether MLB improves renal hemodynamics, oxygen consumption and subsequently attenuates hypoxia in rats induced by 5/6th renal Ablation/Infarction(A/I). Methods Chronic renal failure (CRF) was induced in male SD rats by the 5/6 (A/I) surgery. 30 rats were randomly divided into three groups: sham group, 5/6 (A/I) + vehicle group (CRF group) and 5/6 (A/I) + MLB (CRF + MLB) group. 28 days after the surgery, rats were given with saline or 100 mg/kg MLB by i.p. injection for 8 weeks. The 24-h urinary protein (24hUp), serum creatinine (Scr), blood urine nitrogen (BUN), systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured. The protein expression of Fibronectin (FN), Collagen-I (Col-I), Connective Tissue Growth Factor(CTGF) and Interleukin-6 (IL-6) were measured by Western blot. Renal blood flow (RBF) and renal O2 consumption (QO2) indicated as sodium reabsorption (QO2/TNa) were detected before sacrifice. Renal hypoxia was assessed by measuring the protein expression of nNOS, HIF-1α and VEGF. Results MLB significantly reduced 24hUp, Scr, BUN, SBP and DBP levels in rats with CRF. The expression of FN, Col-I, CTGF and IL-6 were down-regulated by MLB treatment in rats with CRF. In comparison to sham operated rats, 5/6 (A/I) rats had significantly lower RBF, and MLB significantly increased RBF in rats with CRF. Moreover, QO2/TNa was higher in the CRF group as compared to that in the sham group, and it was significantly attenuated in the CRF + MLB group. MLB reversed the expression of nNOS (neuronal nitric oxide synthase), HIF-1α (hypoxia inducible factor-1) and VEGF in rats with CRF. Conclusions MLB improves renal function, fibrosis and inflammation in CRF rats induced by 5/6 (A/I), which is probably related to the increase in RBF, reduction of oxygen consumption and attenuation of renal hypoxia in the remnant kidney with CRF.

Preclinical studies have shown that anti-cytokine therapies could alter drug dispositions through affecting cytochrome P450 synthesis; however, evidence and case reports evaluating clinical relevance of this interaction are scarce. This is the first reported case of interaction between cyclosporine (CsA) and etanercept in a 42-year-old male patient with ankylosing spondylitis and immunoglobulin A nephropathy in whom cytokine levels were monitored both before and after CsA initiation. The initiation of etanercept led to at least 2.5-folds increase in total clearance of CsA. After comprehensive assessment and stepwise exclusion of alternative causes, it was considered that inflammation resolution with etanercept administration has highly induced clearance of CsA, probably mediated by interleukin-2. The case has shown that co-administration of CsA and anti-cytokine therapies such as etanercept needs close monitoring of trough levels. Physicians and pharmacists should be aware of similar interactions especially when the biological therapy is initiated or discontinued and for patients undergoing acute inflammation phase. Monitoring cytokine levels should be considered when drug-cytokine interaction is suspected.

RNA-seq is a powerful tool to investigate how drugs affect the transcriptome but library construction can be costly. Here the authors introduce DRUG-seq, an automated platform for high-throughput transcriptome profiling.

Background: To investigate the expression of long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in renal ischemia-reperfusion injury and explore its role in acute kidney injury. Methods: 18 mice were randomly divided into a sham operation group (Sham) and an ischemia-reperfusion group (IR) in which animals were sacrificed at 6 h or 12 h after surgery. The kidneys were harvested to measure the expression of MALAT1 mRNA. HK2 cells were treated with cobalt chloride (CoCl2) to mimic hypoxia or transfected with siRNA to knockdown MALAT1 before CoCl2 treatment. After that, MALAT1 was analyzed by RT-PCR (reverse transcription-polymerase chain reaction). HIF-1ɑ (hypoxia-inducible factor-1 alpha) and NF-κB (nuclear factor-kappa B) was measured by Western blot. The concentrations of IL-6 (interleukin-6) and TNF-ɑ (tumor necrosis factor-alpha) in the media were detected by ELISA (enzyme-linked immunosorbent assay). Results: The expression of MALAT1 in the IR (6 h/12 h) group was significantly higher than that in the sham group. In HK2 cells, MALAT1 was significantly increased at 1 h, 3 h, and 6 h after CoCl2 treatment but had reduced to the basal level at 12 h and 24 h. Knockdown of MALAT1 by siRNA significantly up-regulated the expression of HIF-1ɑ and NF-κB proteins in CoCl2-treated HK2 cells. In addition, the concentrations of IL-6 and TNF-ɑ were increased by MALAT1 siRNA transfection in CoCl2-treated HK2 cells. Conclusion: The expression of MALAT1 is increased in renal ischemia-reperfusion injury. It is likely that MALAT1 inhibits the hypoxia-induced inflammatory response through the NF-κB pathway.

Summary: Human pluripotent stem cells (hPSCs) generate a variety of disease-relevant cells that can be used to improve the translation of preclinical research. Despite the potential of hPSCs, their use for genetic screening has been limited by technical challenges. We developed a scalable and renewable Cas9 and sgRNA-hPSC library in which loss-of-function mutations can be induced at will. Our inducible mutant hPSC library can be used for multiple genome-wide CRISPR screens in a variety of hPSC-induced cell types. As proof of concept, we performed three screens for regulators of properties fundamental to hPSCs: their ability to self-renew and/or survive (fitness), their inability to survive as single-cell clones, and their capacity to differentiate. We identified the majority of known genes and pathways involved in these processes, as well as a plethora of genes with unidentified roles. This resource will increase the understanding of human development and genetics. This approach will be a powerful tool to identify disease-modifying genes and pathways. : Ihry et al. develop a CRISPR/Cas9 genetic screening platform for hPSCs that enables unbiased genome-scale genetic screening. The platform exhibits high performance and accurately detects the dropout of essential genes. Furthermore, proof-of-concept screens exploit hPSC-specific phenotypes to identify regulators of fitness, survival after single-cell dissociation, and pluripotency. Keywords: CRISPR genome-wide screening, human pluripotent stem cells, iPSC, hESC, PAWR, PMAIP1, DDR

BACKGROUND: The effects of mannitol administration on acute kidney injury (AKI) prevention remain uncertain, as the results from clinical studies were conflicting. Due to the lack of strong evidence, the KDIGO Guideline for AKI did not propose completely evidence-based recommendations on this issue. METHODS: We searched PubMed, EMBASE, clinicaltrials.gov and Cochrane Controlled Trials Register. Randomized controlled trials on adult patients at increased risk of AKI were considered on the condition that they compared the effects of intravascular administration of mannitol plus expansion of intravascular volume with expansion of intravascular volume alone. We calculated pooled risk ratios, numbers needed to treat and mean differences with 95% confidence intervals for dichotomous data and continuous data, respectively. RESULTS: Nine trials involving 626 patients were identified. Compared with expansion of intravascular volume alone, mannitol infusion for AKI prevention in high-risk patients can not reduce the serum creatinine level (MD 1.63, 95% CI -6.02 to 9.28). Subgroup analyses demonstrated that serum creatinine level is negatively affected by the use of mannitol in patients undergoing an injection of radiocontrast agents (MD 17.90, 95% CI 8.56 to 27.24). Mannitol administration may reduce the incidence of acute renal failure or the need of dialysis in recipients of renal transplantation (RR 0.34, 95% CI 0.21 to 0.57, NNT 3.03, 95% CI 2.17 to 5.00). But similar effects were not found in patients at high AKI risk, without receiving renal transplantation (RR 0.29, 95% CI 0.01 to 6.60). CONCLUSIONS: Intravascular administration of mannitol does not convey additional beneficial effects beyond adequate hydration in the patients at increased risk of AKI. For contrast-induced nephropathy, the use of mannitol is even detrimental. Further research evaluating the efficiency of mannitol infusions in the recipients of renal allograft should be undertaken.

BackgroundIdiopathic membranous nephropathy (IMN) is the most common pathological type for nephrotic syndrome in adults in western countries and China. The benefits and harms of immunosuppressive treatment in IMN remain controversial.ObjectivesTo assess the efficacy and safety of different immunosuppressive agents in the treatment of nephrotic syndrome caused by IMN.MethodsPubMed, EMBASE, Cochrane Library and wanfang, weipu, qinghuatongfang, were searched for relevant studies published before December 2011. Reference lists of nephrology textbooks, review articles were checked. A meta-analysis of randomized controlled trials (RCTs) meeting the criteria was performed using Review Manager.Main results17 studies were included, involving 696 patients. Calcineurin inhibitors had a better effect when compared to alkylating agents, on complete remission (RR 1.61, 95% CI 1.13, to 2.30 P = 0.008), partial or complete remission (effective) (CR/PR, RR 1.29, 95% CI 1.09 to 1.52 P = 0.003), and fewer side effects. Among calcineurin inhibitors, tacrolimus (TAC) was shown statistical significance in inducing more remissions. When compared to cyclophosphamide (CTX), leflunomide (LET) showed no beneficial effect, mycophenolate mofetil (MMF) showed significant beneficial on effectiveness (CR/PR, RR: 1.41, 95% CI 1.16 to 1.72 P = 0.0006) but not significant on complete remission (CR, RR: 1.38, 95% CI 0.89 to 2.13 P = 0.15).ConclusionsThis analysis based on Chinese adults and short duration RCTs suggested calcineurin inhibitors, especially TAC, were more effective in proteinuria reduction in IMN with acceptable side effects. Long duration RCTs were needed to confirm the long-term effects of those agents in nephrotic IMN.

Introduction: STAT4 is a transcriptional regulator that has been reported to have oncogenic activities in various cancers. In our study, the posttranscriptional regulatory effect of miR-200a-3p on STAT4 and the prognostic significance of miR-200a-3p and STAT4 were evaluated in bladder cancer (BCa). Material and methods: Proliferation and apoptosis of BCa cell lines were monitored using CCK-8 and Annexin V-FITC assays, respectively. Gene and protein expression levels in BCa tissues and cells were detected using RTqPCR and western blotting, respectively. Results: Significant downregulation of miR-200a-3p and upregulation of STAT4 were observed in BCa tissues and cells compared with the corresponding non-tumor adjacent tissues. Both STAT4 and miR-200a-3p were validated as independent prognostic indicators in sixty-nine BCa patients for predicting overall survival and disease-free survival. In vitro experimental analyses revealed that knockdown of STAT4 repressed BCa cell growth and elevated cell apoptosis. Molecular interactive analysis revealed STAT4 as a direct target of miR-200a-3p, which could suppress STAT4 protein expression by posttranscriptional repression. Cotransfection of miR-200a-3p mimics and STAT4 overexpression plasmids into BCa cells demonstrated that the antineoplastic activities of miR-200a-3p in vitro were neutralized by overexpressed STAT4. Conclusions: The miR-200a-3p/STAT4 signaling cascade plays an important role in the progression of BCa, which provides a new promising target for targeted BCa therapies. [ABSTRACT FROM AUTHOR]