Explore the vast range of titles available.

The pathogenesis of Diabetic kidney disease(DKD) involves pathological changes in both tubulo‐interstitium and the glomerulus. Surprisingly, tubulo‐interstitial fibrosis (TIF), does not develop significantly until the late stage of DKD. Here, it is demonstrated that PR domain‐containing 16 (PRDM16) is a key to the low level of TIF in DKD. In the experiments, PRDM16 is upregulated in high glucose‐treated renal tubular cells, DKD mouse kidneys, and renal biopsy of human DKD patients via activation of NF‐κB signal pathway. High glucose‐induced expression of fibrotic proteins in renal tubular cells is suppressed by PRDM16. Mechanistically, PRDM16 bound to the promotor region of Transient receptor potential ankyrin 1 (TRPA1) to transactivate its expression and then suppressed MAPK (P38, ERK1/2) activation and downstream expression of TGF‐β1. Knockout of PRDM16 from kidney proximal tubules in mice blocked TRPA1 expression and enhanced MAPK activation, TGF‐β1 production, TIF development, and DKD progression, whereas knock‐in of PRDM16 has opposite effects. In addition, overexpression of PRDM16 or its induction by formononetin ameliorated renal dysfunction and fibrosis in db/db diabetic mice. Finally, the above finding are detected in renal biopsies of DKD patients. Together, these results unveil PRDM16/TRPA1 as the mechanism responsible for the low level of TIF in the early stage of DKD by suppressing and TGF‐β1 expression. aPRDM16 is induced in DKD models and human DKD patients. Upon induction, PRDM16 suppresses renal fibrosis. Mechanistically, PRDM16 transactivates TRPA1, which suppresses the pro‐fibrotic pathway of MAPK /TGF‐β1. Thus, the work has unveiled an anti‐fibrosis mechanism that is activated in renal tubular cells to keep TIF during the development of DKD, suggesting new therapeutic targets and strategies.

Background: Transbronchial lung cryobiopsy (TBLC) has widely used for the diagnosis of diffuse lung disease. However, it remains unclear whether TBLC is useful for the diagnosis in hypersensitivity pneumonitis (HP). Methods: We investigated 18 patients who underwent TBLC and were diagnosed with HP based on pathology or multidisciplinary discussion (MDD). Of the 18 patients, 12 had fibrotic HP (fHP), 2 had non-fibrotic HP (non-fHP) diagnosed with MDD. The remaining 4 patients were diagnosed with fHP by pathology but not by MDD because of clinical features. The radiology and pathology of these cases were compared. Results: All patients with fHP showed radiological findings of inflammation, fibrosis, and airway disease. Conversely, pathology showed fibrosis and inflammation in 11 of 12 cases (92%), but airway disease was significantly less common with 5 cases (42%) (p = 0.014). Non-fHP showed inflammatory cell infiltration mainly in the centrilobule on pathology, which was consistent with radiology. Granulomas were found in 5 patients with HP (36%). In the non-HP group, airway-centered interstitial fibrosis was observed in 3 patients (75%) with pathology. Conclusions: The pathology with TBLC is difficult to evaluate airway disease of HP. We need to understand this characteristic of TBLC to make a MDD diagnosis of HP.

BackgroundUncertainty exists regarding the clinical relevance of exercise training across the range of interstitial lung diseases (ILDs).ObjectiveTo establish the impact of exercise training in patients with ILDs of differing aetiology and severity.Methods142 participants with ILD (61 idiopathic pulmonary fibrosis (IPF), 22 asbestosis, 23 connective tissue disease-related ILD (CTD-ILD) and 36 with other aetiologies) were randomised to either 8 weeks of supervised exercise training or usual care. Six-minute walk distance (6MWD), Chronic Respiratory Disease Questionnaire (CRDQ), St George Respiratory Questionnaire IPF-specific version (SGRQ-I) and modified Medical Research Council dyspnoea score were measured at baseline, 9 weeks and 6 months.Measurements and main resultsExercise training significantly increased 6MWD (25 m, 95% CI 2 to 47 m) and health-related quality of life (CRDQ and SGRQ-I) in people with ILD. Larger improvements in 6MWD, CRDQ, SGRQ-I and dyspnoea occurred in asbestosis and IPF compared with CTD-ILD, but with few significant differences between subgroups. Benefits declined at 6 months except in CTD-ILD. Lower baseline 6MWD and worse baseline symptoms were associated with greater benefit in 6MWD and symptoms following training. Greater gains were seen in those whose exercise prescription was successfully progressed according to the protocol. At 6 months, sustained improvements in 6MWD and symptoms were associated with better baseline lung function and less pulmonary hypertension.ConclusionsExercise training is effective in patients across the range of ILDs, with clinically meaningful benefits in asbestosis and IPF. Successful exercise progression maximises improvements and sustained treatment effects favour those with milder disease.Trial registration numberResults, ACTRN12611000416998.

Background The study aimed to explore the relationship between neutrophil‐lymphocyte ratio(NLR) in peripheral blood and renal tubular atrophy/interstitial fibrosis and to evaluate the clinical significance of NLR in IgA nephropathy (IgAN) patients. Methods A Total of 263 IgAN patients were included. The participants were categorized into four groups based on quartile of NLR. The clinical data, pathological features, and 2‐year renal survival rates were compared among the four groups. The independent factors affecting renal tubular atrophy/interstitial fibrosis in IgAN were determined by multivariate linear regression analysis. Results The percentage of renal tubular atrophy/interstitial fibrosis increased with the increase of NLR level (p=0.003). The tubular atrophy/interstitial fibrosis score T1 and T2 in Group Q4 was 40%, which was higher than that of other groups, especially Group Q1 (22.73%, p=0.033) and Group Q3 (22.39%, p=0.029). NLR [β=1.230, 95%CI (0.081, 2.379), p=0.036] might be an independent factor affecting renal tubular atrophy/interstitial fibrosis in IgAN. The area under curve predicted by NLR was 0.596 (95%CI 0.534~0.656, p=0.007) with the specificity 88.24% and the optimal critical value of NLR 3.25. Fourteen patients progressed to end‐stage renal disease within 2 years, and the 2‐year survival rate of kidney was 93.49%. The renal survival rate in Group Q4 was 87.04%, lower than that in other three groups, especially Group Q1 (98.11%, p=0.029). Conclusion NLR was correlated with the level of renal tubular atrophy/interstitial fibrosis and might be a significant factor for predicting the prognosis in the IgAN. Background: IgA nephropathy (IgAN) is an important cause of the end stage renal disease (ESRD). The study aimed to explore the relationship between neutrophil‐lymphocyte ratio (NLR) in peripheral blood and renal tubular atrophy/interstitial fibrosis, and to evaluate the clinical significance of NLR in IgA nephropathy (IgAN) patients. Methods: Total 263 IgAN patients confirmed by renal biopsy pathology were included from January 2013 to May 2018 in Ningbo Hwamei Hospital, University of Chinese Academy of Sciences. The peripheral blood samples were taken from these participants and the NLR was analyzed. The participants were categorized into four groups based on the median and upper and lower quartile of NLR, which were Group Q1 (NLR<1.64), Group Q2 (1.64≤NLR<2.19), Group Q3 (2.19≤NLR<3.00), and Group Q4 (NLR≥3.00), respectively. The clinical data and pathological features were compared among four groups. The independent factors affecting renal tubular atrophy/interstitial fibrosis in IgAN were determined by multivariate linear regression analysis. The diagnostic ability of NLR for renal tubular atrophy/interstitial fibrosis was evaluated by the area under receiver operating characteristic curve (AUC). The 2‐year renal survival rates were compared among the four groups. Results: The levels of white blood cell count, neutrophil count, highly sensitive C‐reactive protein, and the percentage of renal tubular atrophy/interstitial fibrosis were increased while lymphocyte count and estimated glomerular filtration rate were decreased with the increase of NLR level (P < 0.05). The percentage of tubular atrophy/interstitial fibrosis 26%–50% (T1) and >50% (T2) in Group Q4 was 40%, which was higher than that of other groups, especially Group Q1 (22.73%) and Group Q3 (22.39%), with significant difference (P < 0.05). NLR [β = 1.230, 95%CI (0.081, 2.379), P = 0.036] might be an independent factor affecting renal tubular atrophy/interstitial fibrosis in IgAN according to multivariate linear regression analysis results. The AUC predicted by NLR was 0.596 (95%CI 0.534~0.656, P = 0.007) with the specificity 88.24%, the sensitivity 30.00% and the optimal critical value of NLR 3.25. Fourteen patients progressed to end‐stage renal disease within 2 years; and the 2‐year survival rate of kidney was 93.49%. The renal survival rate in Group Q4 was 87.04%, lower than that in other three groups, especially Group Q1 (98.11%), with significant difference (P < 0.05). Conclusion: NLR was correlated with the level of renal tubular atrophy/interstitial fibrosis and might be an significant factor for predicting the prognosis in IgAN. The study aimed to explore the relationship between NLR in peripheral blood and renal tubular atrophy/interstitial fibrosis, and to evaluate the clinical significance of NLR in IgAN patients.

The risk factors for development of fibrotic-like radiographic abnormalities after severe COVID-19 are incompletely described and the extent to which CT findings correlate with symptoms and physical function after hospitalisation remains unclear. At 4 months after hospitalisation, fibrotic-like patterns were more common in those who underwent mechanical ventilation (72%) than in those who did not (20%). We demonstrate that severity of initial illness, duration of mechanical ventilation, lactate dehydrogenase on admission and leucocyte telomere length are independent risk factors for fibrotic-like radiographic abnormalities. These fibrotic-like changes correlate with lung function, cough and measures of frailty, but not with dyspnoea.

BackgroundRelatives of patients with familial interstitial pneumonia (FIP) are at increased risk for pulmonary fibrosis. We assessed the prevalence and risk factors for preclinical pulmonary fibrosis (PrePF) in first-degree relatives of patients with FIP and determined the utility of deep learning in detecting PrePF on CT.MethodsFirst-degree relatives of patients with FIP over 40 years of age who believed themselves to be unaffected by pulmonary fibrosis underwent CT scans of the chest. Images were visually reviewed, and a deep learning algorithm was used to quantify lung fibrosis. Genotyping for common idiopathic pulmonary fibrosis risk variants in MUC5B and TERT was performed.FindingsIn 494 relatives of patients with FIP from 263 families of patients with FIP, the prevalence of PrePF on visual CT evaluation was 15.6% (95% CI 12.6 to 19.0). Compared with visual CT evaluation, deep learning quantitative CT analysis had 84% sensitivity (95% CI 0.72 to 0.89) and 86% sensitivity (95% CI 0.83 to 0.89) for discriminating subjects with visual PrePF diagnosis. Subjects with PrePF were older (65.9, SD 10.1 years) than subjects without fibrosis (55.8 SD 8.7 years), more likely to be male (49% vs 37%), more likely to have smoked (44% vs 27%) and more likely to have the MUC5B promoter variant rs35705950 (minor allele frequency 0.29 vs 0.21). MUC5B variant carriers had higher quantitative CT fibrosis scores (mean difference of 0.36%), a difference that remains significant when controlling for age and sex.InterpretationPrePF is common in relatives of patients with FIP. Its prevalence increases with age and the presence of a common MUC5B promoter variant. Quantitative CT analysis can detect these imaging abnormalities.

BackgroundIdiopathic pulmonary fibrosis (IPF) is a respiratory disorder with a poor prognosis. Our objective is to assess the comparative effectiveness of 22 approved or studied IPF drug treatments.MethodsWe searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and clinicaltrials.gov from inception to 2 April 2021. We included randomised controlled trials (RCTs) for adult patients with IPF receiving one or more of 22 drug treatments. Pairs of reviewers independently identified randomised trials that compared one or more of the target medical treatments in patients with IPF. We assessed the certainty of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach for network meta-analysis. We calculated pooled relative risk (RR) ratios and presented direct or network estimates with 95% credibility intervals (95% CI), within the GRADE framework.ResultsWe identified 48 (10 326 patients) eligible studies for analysis. Nintedanib [RR 0.69 (0.44 to 1.1), pirfenidone [RR 0.63 (0.37 to 1.09); direct estimate), and sildenafil [RR (0.44 (0.16 to 1.09)] probably reduce mortality (all moderate certainty). Nintedanib (2.92% (1.51 to 4.14)), nintedanib+sildenafil (157 mL (–88.35 to 411.12)), pirfenidone (2.47% (–0.1 to 5)), pamrevlumab (4.3% (0.5 to 8.1)) and pentraxin (2.74% (1 to 4.83)) probably reduce decline of overall forced vital capacity (all moderate certainty). Only sildenafil probably reduces acute exacerbation and hospitalisations (moderate certainty). Corticosteroids+azathioprine+N-acetylcysteine increased risk of serious adverse events versus placebo (high certainty).Conclusion and relevanceFuture guidelines should consider sildenafil for IPF and further research needs to be done on promising IPF treatments such as pamrevlumab and pentraxin as phase 3 trials are completed.

IntroductionPersisting respiratory symptoms in COVID-19 survivors may be related to development of pulmonary fibrosis. We assessed the proportion of chest CT scans and pulmonary function tests consistent with parenchymal lung disease in the follow-up of people hospitalised with COVID-19 and viral pneumonitis.MethodsSystematic review and random effects meta-analysis of proportions using studies of adults hospitalised with SARS-CoV-2, SARS-CoV, MERS-CoV or influenza pneumonia and followed up within 12 months. Searches performed in MEDLINE and Embase. Primary outcomes were proportion of radiological sequelae on CT scans; restrictive impairment; impaired gas transfer. Heterogeneity was explored in meta-regression.ResultsNinety-five studies (98.9% observational) were included in qualitative synthesis, 70 were suitable for meta-analysis including 60 SARS-CoV-2 studies with a median follow-up of 3 months. In SARS-CoV-2, the overall estimated proportion of inflammatory sequelae was 50% during follow-up (0.50; 95% CI 0.41 to 0.58; I2=95%), fibrotic sequelae were estimated in 29% (0.29; 95% CI 0.22 to 0.37; I2=94.1%). Follow-up time was significantly associated with estimates of inflammatory sequelae (−0.036; 95% CI −0.068 to –0.004; p=0.029), associations with fibrotic sequelae did not reach significance (−0.021; 95% CI −0.051 to 0.009; p=0.176). Impaired gas transfer was estimated at 38% of lung function tests (0.38 95% CI 0.32 to 0.44; I2=92.1%), which was greater than restrictive impairment (0.17; 95% CI 0.13 to 0.23; I2=92.5%), neither were associated with follow-up time (p=0.207; p=0.864).DiscussionSequelae consistent with parenchymal lung disease were observed following COVID-19 and other viral pneumonitis. Estimates should be interpreted with caution due to high heterogeneity, differences in study casemix and initial severity.PROSPERO registration numberCRD42020183139.

BackgroundPrior work suggests different interstitial lung diseases (ILDs) that share the radiological usual interstitial pneumonia (UIP) pattern have an overall worse prognosis. However, epidemiological data with longitudinal sampling and replication remains lacking.MethodsData was used from the Pulmonary Fibrosis Foundation Patient Registry (PFF-PR) (n=932) and a meta-cohort of ILD research studies (n=1579). Linear mixed-effects models and Cox proportional hazard models were used to determine forced vital capacity (FVC) slopes and 5-year transplant-free survival, respectively, by ILD diagnosis and UIP radiological pattern. Secondarily, we examined FVC and survival by diagnosis and radiological fibrosis quantified by data-driven texture analysis (DTA) in the PFF-PR. Models were adjusted for age, sex, smoking and antifibrotic and immunosuppression medication use.ResultsThe proportions of idiopathic pulmonary fibrosis (IPF), fibrotic hypersensitivity pneumonitis (FHP) and connective tissue disease (CTD)-ILD were the following for PFF-PR (70%, 11%, 19%) and meta-cohort (21%, 32%, 47%). In the PFF-PR, CTD-ILD with UIP CT pattern was associated with slower FVC decline (−34.4 mL/year) compared with IPF (−158.4 mL/year) and longer transplant-free survival (HR 0.50, 95% CI 0.29 to 0.85). This was replicated in the meta cohort for FVC (−53.1 vs −185.9 mL/year, p<0.0001) and survival (HR 0.38, 95% CI 0.27 to 0.53). A similar pattern was seen using DTA to objectively categorise patients into higher and lower radiological fibrosis. Between IPF and FHP-UIP, FVC decline was not significantly different in the PFF-PR (−203.4 vs −158.4 mL/year, p=0.58) and meta-cohort (−124.0 vs −185.9 mL/year, p=0.25).ConclusionsEven in the presence of a UIP CT pattern, there may still be differences in lung function over time and survival, particularly for CTD-ILD.

IntroductionIdiopathic pulmonary fibrosis (IPF) is a progressive fibrosing interstitial lung disease of unknown aetiology and cure. Recent studies have reported a dysregulation of exosomal microRNAs (miRs) in the IPF context. However, the impact of IPF-related exosomal miRs on the progression of pulmonary fibrosis is unknown.MethodsTwo independent cohorts were enrolled at the ambulatory care polyclinic of Liège University. Exosomes from sputum were obtained from 19 patients with IPF and 23 healthy subjects (HSs) (cohort 1), and the ones from plasma derived from 14 patients with IPF and 14 HSs (cohort 2). Exosomal miR expression was performed by quantitative reverse transcription–PCR. The functional role of exosomal miRs was assessed in vitro by transfecting miR mimics in human alveolar epithelial cells and lung fibroblasts.ResultsExosomal miR analysis showed that miR-142-3p was significantly upregulated in sputum and plasma of patients with IPF (8.06-fold, p<0.0001; 1.64 fold, p=0.008, respectively). Correlation analysis revealed a positive association between exosomal miR-142-3p and the percentage of macrophages from sputum of patients with IPF (r=0.576, p=0.012), suggesting macrophage origin of exosomal miR-142-3p upregulation. The overexpression of miR-142-3p in alveolar epithelial cells and lung fibroblasts was able to reduce the expression of transforming growth factor β receptor 1 (TGFβ-R1) and profibrotic genes. Furthermore, exosomes isolated from macrophages present antifibrotic properties due in part to the repression of TGFβ-R1 by miR-142-3p transfer in target cells.DiscussionOur results suggest that macrophage-derived exosomes may fight against pulmonary fibrosis progression via the delivery of antifibrotic miR-142–3 p to alveolar epithelial cells and lung fibroblasts.