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AbstractObjectiveTo examine the protective effects of appropriate personal protective equipment for frontline healthcare professionals who provided care for patients with coronavirus disease 2019 (covid-19).DesignCross sectional study.SettingFour hospitals in Wuhan, China.Participants420 healthcare professionals (116 doctors and 304 nurses) who were deployed to Wuhan by two affiliated hospitals of Sun Yat-sen University and Nanfang Hospital of Southern Medical University for 6-8 weeks from 24 January to 7 April 2020. These study participants were provided with appropriate personal protective equipment to deliver healthcare to patients admitted to hospital with covid-19 and were involved in aerosol generating procedures. 77 healthcare professionals with no exposure history to covid-19 and 80 patients who had recovered from covid-19 were recruited to verify the accuracy of antibody testing.Main outcome measuresCovid-19 related symptoms (fever, cough, and dyspnoea) and evidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, defined as a positive test for virus specific nucleic acids in nasopharyngeal swabs, or a positive test for IgM or IgG antibodies in the serum samples.ResultsThe average age of study participants was 35.8 years and 68.1% (286/420) were women. These study participants worked 4-6 hour shifts for an average of 5.4 days a week; they worked an average of 16.2 hours each week in intensive care units. All 420 study participants had direct contact with patients with covid-19 and performed at least one aerosol generating procedure. During the deployment period in Wuhan, none of the study participants reported covid-19 related symptoms. When the participants returned home, they all tested negative for SARS-CoV-2 specific nucleic acids and IgM or IgG antibodies (95% confidence interval 0.0 to 0.7%).ConclusionBefore a safe and effective vaccine becomes available, healthcare professionals remain susceptible to covid-19. Despite being at high risk of exposure, study participants were appropriately protected and did not contract infection or develop protective immunity against SARS-CoV-2. Healthcare systems must give priority to the procurement and distribution of personal protective equipment, and provide adequate training to healthcare professionals in its use.

In this trial, patients with CKD (with or without type 2 diabetes) were randomly assigned to receive dapagliflozin or placebo. The primary composite outcome — a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes — was less frequent with dapagliflozin.

The number of patients on hemodialysis (HD) is rapidly increasing in China. As an Asian country with a large number of HD patients, understanding the status of Chinese HD patients has a special significance. We reported here the baseline data for China Dialysis Outcomes and Practice Pattern Study Phase 5 (DOPPS5). The DOPPS is an international prospective, observational cohort study. Patients were restricted to the initial sample of patients who participated in China DOPPS5. We summarized the baseline demographic and clinical data of patients. Results were weighted by facility sampling fraction. 1186 patients were initial patients in China DOPPS5. The mean age was 58.7 ± 3.5 years, with 54.6% males. The median dialysis vintage was 3.4 (1.5, 6.3) years. The main assigned primary end-stage kidney disease (ESKD) causes was chronic glomerulonephritis (45.9%), followed by diabetes (19.9%). 17.6% patients had hepatitis B infection, and 10.0% patients had hepatitis C infection. 25.9% patients had a single-pooled Kt/V < 1.2. 86.6% patients had albumin > 3.5 g/dl. 18.8% patients had hemoglobin < 9 g/dl. 66.5% patients had serum calcium in target range (8.4–10.2 mg/dl), 41.5% patients had serum phosphate in target range (3.5–5.5 mg/dl) and 51.2% patients maintained PTH in 150–600 pg/dl. 88.2% patients used fistula as their vascular access. Meanwhile, there were differences in the demographic, clinical, laboratory, and treatment characteristics among the three cities participated in China DOPPS. We observed a relatively higher albumin level and a higher rate of fistula usage in our patients. But it remains a major challenge to us on the management of CKD-MBD and anemia. This study did not include patients in small cities and remote areas, where the situation of HD patients might be worse than reported.

We aim to examine the relation of several folate forms (5-methyltetrahydrofolate (5-mTHF), unmetabolised folic acid (UMFA) and MeFox) with kidney function and albuminuria, which remained uncertain. The cross-sectional study was conducted in 18 757 participants from National Health and Nutrition Examination Survey 2011–2018. The kidney outcomes were reduced estimated glomerular filtration rate (eGFR) (<60 ml/min/1·73 m2), microalbuminuria (albumin:creatinine ratio (ACR) of 30–299 mg/g) and macroalbuminuria (ACR ≥ 300 mg/g). Overall, there were significant inverse associations between serum 5-mTHF and kidney outcomes with significant lower prevalence of reduced eGFR (OR, 0·71; 95 % CI: 0·57, 0·87) and macroalbuminuria (OR, 0·65; 95 % CI: 0·46, 0·91) in participants in quartiles 3–4 (v. quartiles 1–2; both P for trend across quartiles <0·05). In contrast, there were significant positive relationship between serum UMFA and kidney outcomes with significant higher prevalence of reduced eGFR in participants in quartiles 2–4 (v. quartile 1; OR, 2·12; 95 % CI: 1·45, 3·12; P for trend <0·001) and higher prevalence of macroalbuminuria in participants in quartile 4 (v. quartiles 1–3; OR, 1·46; 95 % CI: 1·06, 2·01; P for trend <0·001). However, there was no significant associations of 5-mTHF and UMFA with microalbuminuria. In addition, there were significant positive relationships of serum MeFox with reduced eGFR, microalbuminuria and macroalbuminuria (all P for trend <0·01). In conclusion, higher 5-mTHF level, along with lower UMFA and MeFox level, was associated with lower prevalence of kidney outcomes, which may help counsel future clinical trials and nutritional guidelines regarding the folate supplement.

Renal fibrosis is the common pathological feature in a variety of chronic kidney diseases. Aging is highly associated with the progression of renal fibrosis. Among several determinants, mitochondrial dysfunction plays an important role in aging. However, the underlying mechanisms of mitochondrial dysfunction in age‐related renal fibrosis are not elucidated. Herein, we found that Wnt/β‐catenin signaling and renin–angiotensin system (RAS) activity were upregulated in aging kidneys. Concomitantly, mitochondrial mass and functions were impaired with aging. Ectopic expression of Klotho, an antagonist of endogenous Wnt/β‐catenin activity, abolished renal fibrosis in d‐galactose (d‐gal)‐induced accelerated aging mouse model and significantly protected renal mitochondrial functions by preserving mass and diminishing the production of reactive oxygen species. In an established aging mouse model, dickkopf 1, a more specific Wnt inhibitor, and the mitochondria‐targeted antioxidant mitoquinone restored mitochondrial mass and attenuated tubular senescence and renal fibrosis. In a human proximal tubular cell line (HKC‐8), ectopic expression of Wnt1 decreased biogenesis and induced dysfunction of mitochondria, and triggered cellular senescence. Moreover, d‐gal triggered the transduction of Wnt/β‐catenin signaling, which further activated angiotensin type 1 receptor (AT1), and then decreased the mitochondrial mass and increased cellular senescence in HKC‐8 cells and primary cultured renal tubular cells. These effects were inhibited by AT1 blocker of losartan. These results suggest inhibition of Wnt/β‐catenin signaling and the RAS could slow the onset of age‐related mitochondrial dysfunction and renal fibrosis. Taken together, our results indicate that Wnt/β‐catenin/RAS signaling mediates age‐related renal fibrosis and is associated with mitochondrial dysfunction. Wnt/β‐catenin signaling induces RAS activation, which promotes cellular senescence and age‐related kidney fibrosis in association with mitochondrial dysfunction that stems from a loss of mitochondrial biogenesis.

Detection of asymptomatic or subclinical novel human coronavirus SARS-CoV-2 infection is critical for understanding the overall prevalence and infection potential of COVID-19. To estimate the cumulative prevalence of SARS-CoV-2 infection in China, we evaluated the host serologic response, measured by the levels of immunoglobulins M and G in 17,368 individuals, in the city of Wuhan, the epicenter of the COVID-19 pandemic in China, and geographic regions in the country, during the period from 9 March 2020 to 10 April 2020. In our cohorts, the seropositivity in Wuhan varied between 3.2% and 3.8% in different subcohorts. Seroposivity progressively decreased in other cities as the distance to the epicenter increased. Patients who visited a hospital for maintenance hemodialysis and healthcare workers also had a higher seroprevalence of 3.3% (51 of 1,542, 2.5–4.3%, 95% confidence interval (CI)) and 1.8% (81 of 4,384, 1.5–2.3%, 95% CI), respectively. More studies are needed to determine whether these results are generalizable to other populations and geographic locations, as well as to determine at what rate seroprevalence is increasing with the progress of the COVID-19 pandemic. Serologic surveillance has the potential to provide a more faithful cumulative viral attack rate for the first season of this novel SARS-CoV-2 infection. Initial results of serological surveillance in China provide valuable data for estimation of the cumulative prevalence of SARS-CoV-2 infection in the general population.

Loss of Klotho, an anti-aging protein, plays a critical role in the pathogenesis of chronic kidney diseases. As Klotho is a large transmembrane protein, it is challenging to harness it as a therapeutic remedy. Here we report the discovery of a Klotho-derived peptide 1 (KP1) protecting kidneys by targeting TGF-β signaling. By screening a series of peptides derived from human Klotho protein, we identified KP1 that repressed fibroblast activation by binding to TGF-β receptor 2 (TβR2) and disrupting the TGF-β/TβR2 engagement. As such, KP1 blocked TGF-β-induced activation of Smad2/3 and mitogen-activated protein kinases. In mouse models of renal fibrosis, intravenous injection of KP1 resulted in its preferential accumulation in injured kidneys. KP1 preserved kidney function, repressed TGF-β signaling, ameliorated renal fibrosis and restored endogenous Klotho expression. Together, our findings suggest that KP1 recapitulates the anti-fibrotic action of Klotho and offers a potential remedy in the fight against fibrotic kidney diseases. Klotho is an anti-ageing protein whose expression is downregulated in chronic kidney disease, but the large size of the protein makes it challenging to deliver therapeutically. Here, the authors develop a Klotho-derived peptide, and show that it recapitulates the anti-fibrotic action of Klotho and prevents kidney fibrosis in mice by targeting TGF-β signalling.

: Renal infiltration of inflammatory cells including macrophages is a crucial event in kidney fibrogenesis. However, how macrophage regulates fibroblast activation in the fibrotic kidney remains elusive. In this study, we show that macrophages promoted fibroblast activation by assembling a vitronectin (Vtn)-enriched, extracellular microenvironment. : We prepared decellularized kidney tissue scaffold (KTS) from normal and fibrotic kidney after unilateral ischemia-reperfusion injury (UIRI) and carried out an unbiased quantitative proteomics analysis. NRK-49F cells were seeded on macrophage-derived extracellular matrix (ECM) scaffold. Genetic Vtn knockout (Vtn-/-) mice and chronic kidney disease (CKD) model with overexpression of Vtn were used to corroborate a role of Vtn/integrin αvβ5/Src in kidney fibrosis. : Vtn was identified as one of the most upregulated proteins in the decellularized kidney tissue scaffold from fibrotic kidney by mass spectrometry. Furthermore, Vtn was upregulated in the kidney of mouse models of CKD and primarily expressed and secreted by activated macrophages. Urinary Vtn levels were elevated in CKD patients and inversely correlated with kidney function. Genetic ablation or knockdown of Vtn protected mice from developing kidney fibrosis after injury. Conversely, overexpression of Vtn exacerbated renal fibrotic lesions and aggravated renal insufficiency. We found that macrophage-derived, Vtn-enriched extracellular matrix scaffold promoted fibroblast activation and proliferation. In vitro, Vtn triggered fibroblast activation by stimulating integrin αvβ5 and Src kinase signaling. Either blockade of αvβ5 with neutralizing antibody or pharmacological inhibition of Src by Saracatinib abolished Vtn-induced fibroblast activation. Moreover, Saracatinib dose-dependently ameliorated Vtn-induced kidney fibrosis in vivo. These results demonstrate that macrophage induces fibroblast activation by assembling a Vtn-enriched extracellular microenvironment, which triggers integrin αvβ5 and Src kinase signaling. : Our findings uncover a novel mechanism by which macrophages contribute to kidney fibrosis via assembling a Vtn-enriched extracellular niche and suggest that disrupting fibrogenic microenvironment could be a therapeutic strategy for fibrotic CKD.

Chronic kidney disease (CKD) has a high prevalence worldwide. Renal fibrosis is the common pathological feature in various types of CKD. However, the underlying mechanisms are not determined. Here, we adopted different CKD mouse models and cultured human proximal tubular cell line (HKC‐8) to examine the expression of C‐X‐C motif chemokine receptor 4 (CXCR4) and β‐catenin signalling, as well as their relationship in renal fibrosis. In CKD mice and humans with a variety of nephropathies, CXCR4 was dramatically up‐regulated in tubules, with a concomitant activation of β‐catenin. CXCR4 expression level was positively correlated with the expression of β‐catenin target MMP‐7. AMD3100, a CXCR4 receptor blocker, and gene knockdown of CXCR4 significantly inhibited the activation of JAK/STAT and β‐catenin signalling, protected against tubular injury and renal fibrosis. CXCR4‐induced renal fibrosis was inhibited by treatment with ICG‐001, an inhibitor of β‐catenin signalling. In HKC‐8 cells, overexpression of CXCR4 induced activation of β‐catenin and deteriorated cell injury. These effects were inhibited by ICG‐001. Stromal cell–derived factor (SDF)‐1α, the ligand of CXCR4, stimulated the activation of JAK2/STAT3 and JAK3/STAT6 signalling in HKC‐8 cells. Overexpression of STAT3 or STAT6 decreased the abundance of GSK3β mRNA. Silencing of STAT3 or STAT6 significantly blocked SDF‐1α‐induced activation of β‐catenin and fibrotic lesions. These results uncover a novel mechanistic linkage between CXCR4 and β‐catenin activation in renal fibrosis in association with JAK/STAT/GSK3β pathway. Our studies also suggest that targeted inhibition of CXCR4 may provide better therapeutic effects on renal fibrosis by inhibiting multiple downstream signalling cascades.

The mechanisms underlying fibrogenic responses after injury are not well understood. Epithelial cell cycle arrest in G2/M after injury is a key checkpoint for determining wound-healing leading to either normal cell proliferation or fibrosis. Here, we identify a kidney- and liver-enriched circular RNA, circBNC2, which is abundantly expressed in normal renal tubular cells and hepatocytes but significantly downregulated after acute ischemic or toxic insult. Loss of circBNC2 is at least partially mediated by upregulation of DHX9. Gain- and loss-of-function studies, both in vitro and in vivo, demonstrate that circBNC2 acts as a negative regulator of cell G2/M arrest by encoding a protein that promotes formation of CDK1/cyclin B1 complexes. Restoring circBNC2 in experimentally-induced male mouse models of fibrotic kidney and liver, decreases G2/M arrested cell numbers with secretion of fibrotic factors, thereby mitigating extracellular matrix deposition and fibrosis. Decreased expression of circBNC2 and increased G2/M arrest of epithelial cells are recapitulated in human ischemic reperfusion injury (IRI)-induced chronic kidney disease and inflammation-induced liver fibrosis, highlighting the clinical relevance. These findings suggest that restoring circBNC2 might represent a potential strategy for therapeutic intervention in epithelial organ fibrosis. G2/M arrest of epithelial cells leads to fibrosis with unclear mechanisms. This study identifies a protein-encoding circRNA, circBNC2, which inhibits epithelial cells G2/M arrest to prevent fibrotic maladaptive repair in damaged kidney and liver, revealing a potential intervention target for fibrosis.