Pub Date : 2025-01-11DOI: 10.1016/j.jcf.2025.01.005
Claire Dumortier, Andrew Frauenpreis, Antony Hoarau, Amy L Ryan, Sophie C Gangloff, Soula Danopoulos, Frédéric Velard, Denise Al Alam
Background: Cystic Fibrosis-related Bone Disease is an emerging challenge faced by 50 % of adult people with cystic fibrosis (CF). The multifactorial causes of this comorbidity remain elusive. However, congenital bone defects have been observed in animal models with CFTR mutations, suggesting its importance. The role of CFTR in bone cells development is unknown. Studies from human cells remain somewhat controversial depending on the cells used and the disease state of the patients from which the cells derived.
Methods: Therefore, we investigated the role of CFTR in osteoblast development using induced pluripotent stem cells generated from homozygous CF donors for F508del and non-CF controls. This approach allows for a clear understanding towards how the CFTR mutation may influence osteoblast differentiation independently from other confounding factors.
Results: We observed a lower capacity of differentiation in CF cells as compared to control, already from mesenchymal stem cells (MSC) stage, whereby they retained expression of the pluripotency marker OCT4. Furthermore, our results demonstrated a delayed osteoblast commitment and altered expression of specific markers, such as an increased RANKL/OPG ratio and decreased BMP2, suggesting a potentially perturbed bone homeostasis associated with CFTR mutation.
Conclusions: This is the first study of its kind, clearly demonstrating a role for CFTR mutation in delaying osteoblast differentiation and/or regeneration.
{"title":"CFTR mutation is associated with bone differentiation abnormalities in cystic fibrosis.","authors":"Claire Dumortier, Andrew Frauenpreis, Antony Hoarau, Amy L Ryan, Sophie C Gangloff, Soula Danopoulos, Frédéric Velard, Denise Al Alam","doi":"10.1016/j.jcf.2025.01.005","DOIUrl":"https://doi.org/10.1016/j.jcf.2025.01.005","url":null,"abstract":"<p><strong>Background: </strong>Cystic Fibrosis-related Bone Disease is an emerging challenge faced by 50 % of adult people with cystic fibrosis (CF). The multifactorial causes of this comorbidity remain elusive. However, congenital bone defects have been observed in animal models with CFTR mutations, suggesting its importance. The role of CFTR in bone cells development is unknown. Studies from human cells remain somewhat controversial depending on the cells used and the disease state of the patients from which the cells derived.</p><p><strong>Methods: </strong>Therefore, we investigated the role of CFTR in osteoblast development using induced pluripotent stem cells generated from homozygous CF donors for F508del and non-CF controls. This approach allows for a clear understanding towards how the CFTR mutation may influence osteoblast differentiation independently from other confounding factors.</p><p><strong>Results: </strong>We observed a lower capacity of differentiation in CF cells as compared to control, already from mesenchymal stem cells (MSC) stage, whereby they retained expression of the pluripotency marker OCT4. Furthermore, our results demonstrated a delayed osteoblast commitment and altered expression of specific markers, such as an increased RANKL/OPG ratio and decreased BMP2, suggesting a potentially perturbed bone homeostasis associated with CFTR mutation.</p><p><strong>Conclusions: </strong>This is the first study of its kind, clearly demonstrating a role for CFTR mutation in delaying osteoblast differentiation and/or regeneration.</p>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-11DOI: 10.1016/j.jcf.2024.12.001
Lucy Perrem, Stephanie Jeanneret-Manning, Stephanie D Davis, Margaret Rosenfeld, Todd Edwards, Sanja Stanojevic, Felix Ratjen
Introduction: The Lung Clearance Index (LCI) is an established research test, but its role in clinical decision-making is not well defined. This study estimated the proportion of treatment decisions that are changed or supported by the added information provided by LCI.
Methods: A mixed methods prospective observational study was conducted in North America. Providers were invited to participate in a clinical vignette survey consisting of 10 hypothetical scenarios involving pediatric cystic fibrosis (CF) management. First, they made a clinical decision based on information captured in routine clinical visits. Then, the LCI value was made available, and providers were asked whether the LCI changed or supported their decision. A prospective study was also conducted at three CF centres to determine how often physicians make pulmonary treatment decisions at CF clinic visits and how often they perceive additional lung function data would be helpful for these decisions.
Results: We received 522 vignette responses from 62 participants. LCI changed the decision in 18.4 % of cases, supported the decision in 57.1 % and did not impact the decision in 24.5 %. Data from patient encounters in the prospective study demonstrated that changes to pulmonary treatments were considered in 98/322 (30.4 %) visits; additional lung function information could potentially have helped in 64.3 % of the treatment decisions.
Conclusion: LCI changes or supports a significant proportion of treatment decisions. Providers perceive that additional information about lung function could be helpful at the majority of encounters where changes in treatment are considered.
{"title":"Does using the Lung Clearance Index (LCI) inform clinical decisions in children with cystic fibrosis?","authors":"Lucy Perrem, Stephanie Jeanneret-Manning, Stephanie D Davis, Margaret Rosenfeld, Todd Edwards, Sanja Stanojevic, Felix Ratjen","doi":"10.1016/j.jcf.2024.12.001","DOIUrl":"https://doi.org/10.1016/j.jcf.2024.12.001","url":null,"abstract":"<p><strong>Introduction: </strong>The Lung Clearance Index (LCI) is an established research test, but its role in clinical decision-making is not well defined. This study estimated the proportion of treatment decisions that are changed or supported by the added information provided by LCI.</p><p><strong>Methods: </strong>A mixed methods prospective observational study was conducted in North America. Providers were invited to participate in a clinical vignette survey consisting of 10 hypothetical scenarios involving pediatric cystic fibrosis (CF) management. First, they made a clinical decision based on information captured in routine clinical visits. Then, the LCI value was made available, and providers were asked whether the LCI changed or supported their decision. A prospective study was also conducted at three CF centres to determine how often physicians make pulmonary treatment decisions at CF clinic visits and how often they perceive additional lung function data would be helpful for these decisions.</p><p><strong>Results: </strong>We received 522 vignette responses from 62 participants. LCI changed the decision in 18.4 % of cases, supported the decision in 57.1 % and did not impact the decision in 24.5 %. Data from patient encounters in the prospective study demonstrated that changes to pulmonary treatments were considered in 98/322 (30.4 %) visits; additional lung function information could potentially have helped in 64.3 % of the treatment decisions.</p><p><strong>Conclusion: </strong>LCI changes or supports a significant proportion of treatment decisions. Providers perceive that additional information about lung function could be helpful at the majority of encounters where changes in treatment are considered.</p>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142971030","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-09DOI: 10.1016/j.jcf.2024.12.004
Noor Elshaar, Cade Hovater, Kasey Raffensperger
{"title":"Pain is a constant in our lives with CF: Please believe us.","authors":"Noor Elshaar, Cade Hovater, Kasey Raffensperger","doi":"10.1016/j.jcf.2024.12.004","DOIUrl":"https://doi.org/10.1016/j.jcf.2024.12.004","url":null,"abstract":"","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142965141","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-09DOI: 10.1016/j.jcf.2024.12.005
Heather Boas, Jesse Y Hsu, Allen Koshy, Semret Seyoum, Marsha Regenstein, Gina Hong, Olivia Dieni, Anne Willis, Clement L Ren
Background: Food insecurity (FI) is more prevalent in people with cystic fibrosis (PwCF) than the reported national prevalence, but there are limited data on the relationship between FI and health outcomes in PwCF. The objective of this study was to analyze the relationship between FI in PwCF and pulmonary and nutritional status.
Methods: We leveraged an electronic cross-sectional survey that ascertained FI status and gave participants the option to link their survey data to their records in the Cystic Fibrosis Foundation Patient Registry (CFFPR). Linear regression and negative binomial models were used to estimate the associations in mean differences between FI and percent predicted FEV1 (ppFEV1), nutritional indices, and hospitalizations.
Results: There were 1,856 respondents, 1,234 (66.5 %) of whom granted permission to link to the CFFPR. FI was present in 352 (28 %) of the respondents. FI was associated with lower ppFEV1 (-6.5; 95 % CI -9.9, -3.1); however, this was no longer statistically significant after adjusting for confounders. FI was independently associated with increased hospitalizations. Higher weight for age was significantly associated with FI in the adjusted model, but there were no significant associations between height for age or absolute weight and body mass index (BMI) in adults.
Conclusions: FI in PwCF is associated with adverse health outcomes. These results support screening for FI during routine visits. Further studies are needed to investigate causal relationships between FI and adverse clinical outcomes.
背景:食物不安全(FI)在囊性纤维化(PwCF)患者中比报道的全国患病率更为普遍,但关于FI与PwCF患者健康结局之间关系的数据有限。本研究的目的是分析PwCF中FI与肺和营养状况的关系。方法:我们利用电子横断面调查来确定FI状态,并让参与者选择将他们的调查数据与他们在囊性纤维化基金会患者登记处(CFFPR)中的记录联系起来。使用线性回归和负二项模型来估计FI与预测FEV1百分比(ppFEV1),营养指数和住院率之间的平均差异的关联。结果:共有1856名受访者,其中1234人(66.5%)同意链接cfpr。352名(28%)受访者出现FI。FI与较低的ppFEV1相关(-6.5;95% ci -9.9, -3.1);然而,在调整混杂因素后,这不再具有统计学意义。FI与住院率增加独立相关。在调整后的模型中,较高的年龄体重与FI显著相关,但成人年龄身高或绝对体重与体重指数(BMI)之间没有显著关联。结论:PwCF患者FI与不良健康结局相关。这些结果支持在常规访问中筛查FI。需要进一步研究FI与不良临床结果之间的因果关系。
{"title":"Clinical features associated with self-reported food insecurity in people with cystic fibrosis.","authors":"Heather Boas, Jesse Y Hsu, Allen Koshy, Semret Seyoum, Marsha Regenstein, Gina Hong, Olivia Dieni, Anne Willis, Clement L Ren","doi":"10.1016/j.jcf.2024.12.005","DOIUrl":"https://doi.org/10.1016/j.jcf.2024.12.005","url":null,"abstract":"<p><strong>Background: </strong>Food insecurity (FI) is more prevalent in people with cystic fibrosis (PwCF) than the reported national prevalence, but there are limited data on the relationship between FI and health outcomes in PwCF. The objective of this study was to analyze the relationship between FI in PwCF and pulmonary and nutritional status.</p><p><strong>Methods: </strong>We leveraged an electronic cross-sectional survey that ascertained FI status and gave participants the option to link their survey data to their records in the Cystic Fibrosis Foundation Patient Registry (CFFPR). Linear regression and negative binomial models were used to estimate the associations in mean differences between FI and percent predicted FEV1 (ppFEV1), nutritional indices, and hospitalizations.</p><p><strong>Results: </strong>There were 1,856 respondents, 1,234 (66.5 %) of whom granted permission to link to the CFFPR. FI was present in 352 (28 %) of the respondents. FI was associated with lower ppFEV1 (-6.5; 95 % CI -9.9, -3.1); however, this was no longer statistically significant after adjusting for confounders. FI was independently associated with increased hospitalizations. Higher weight for age was significantly associated with FI in the adjusted model, but there were no significant associations between height for age or absolute weight and body mass index (BMI) in adults.</p><p><strong>Conclusions: </strong>FI in PwCF is associated with adverse health outcomes. These results support screening for FI during routine visits. Further studies are needed to investigate causal relationships between FI and adverse clinical outcomes.</p>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142965139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-07DOI: 10.1016/j.jcf.2024.12.009
Patricia Gutiérrez, Laura Jiménez, Jessica Martínez, Carmen Alba, María Victoria Girón, Gabriel Olveira, Pedro Ruiz-Esteban, Casilda Olveira
Background: Cystic fibrosis (CF) is caused by variants in a gene that encodes a protein essential for water and ion transport in the epithelial cells of exocrine organs. Given the possible relationship of this protein and conjunctival and corneal epithelium, the aim of this study was to evaluate ophthalmologic alterations in people with CF.
Methods: Forty-five people with CF underwent pulmonary evaluation including inflammatory score (IS). These people along with 98 sex-matched controls underwent ophthalmologic evaluation including dry eye disease (DED) testing, corneal topography using Pentacam™ and macular and peripapillary retinal nerve fiber layer (pRNFL) thickness with optical coherence tomography (OCT).
Results: The CF group presented a higher percentage of pathologic tear break-up time (T-BUT) (55.6 % vs 25 %, p = 0.001) and Schirmer's test 1 (40 % versus 19.4 %, p = 0.009) than the control group. In the CF group, an inverse correlation was observed between T-BUT and IS (r=- 0.373, p = 0.012), as well as T-BUT and peripheral eosinophilia (r=-0.338; p = 0.023). People with CF presented lower values of central corneal thickness (p = 0.009), thinnest point (p = 0.006), anterior chamber volume (p = 0.034), and anterior chamber angle (p = 0.011) than the control group and lower pRNLF thickness in the superior temporal sector (p = 0.002).
Conclusions: Our findings indicate a higher prevalence of dry eye disease (DED) among people with CF compared to controls. The severity of the condition increases with higher systemic inflammation. Additionally, CF may affect the anterior segment of the eye, leading to a reduction in the nerve fiber layer and early signs of glaucoma.
{"title":"Dry eye disease and morphological changes in the anterior chamber in people with cystic fibrosis.","authors":"Patricia Gutiérrez, Laura Jiménez, Jessica Martínez, Carmen Alba, María Victoria Girón, Gabriel Olveira, Pedro Ruiz-Esteban, Casilda Olveira","doi":"10.1016/j.jcf.2024.12.009","DOIUrl":"https://doi.org/10.1016/j.jcf.2024.12.009","url":null,"abstract":"<p><strong>Background: </strong>Cystic fibrosis (CF) is caused by variants in a gene that encodes a protein essential for water and ion transport in the epithelial cells of exocrine organs. Given the possible relationship of this protein and conjunctival and corneal epithelium, the aim of this study was to evaluate ophthalmologic alterations in people with CF.</p><p><strong>Methods: </strong>Forty-five people with CF underwent pulmonary evaluation including inflammatory score (IS). These people along with 98 sex-matched controls underwent ophthalmologic evaluation including dry eye disease (DED) testing, corneal topography using Pentacam™ and macular and peripapillary retinal nerve fiber layer (pRNFL) thickness with optical coherence tomography (OCT).</p><p><strong>Results: </strong>The CF group presented a higher percentage of pathologic tear break-up time (T-BUT) (55.6 % vs 25 %, p = 0.001) and Schirmer's test 1 (40 % versus 19.4 %, p = 0.009) than the control group. In the CF group, an inverse correlation was observed between T-BUT and IS (r=- 0.373, p = 0.012), as well as T-BUT and peripheral eosinophilia (r=-0.338; p = 0.023). People with CF presented lower values of central corneal thickness (p = 0.009), thinnest point (p = 0.006), anterior chamber volume (p = 0.034), and anterior chamber angle (p = 0.011) than the control group and lower pRNLF thickness in the superior temporal sector (p = 0.002).</p><p><strong>Conclusions: </strong>Our findings indicate a higher prevalence of dry eye disease (DED) among people with CF compared to controls. The severity of the condition increases with higher systemic inflammation. Additionally, CF may affect the anterior segment of the eye, leading to a reduction in the nerve fiber layer and early signs of glaucoma.</p>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142949652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-03DOI: 10.1016/j.jcf.2024.12.006
Edith T Zemanick, Bonnie Ramsey, Dorota Sands, Edward F McKone, Isabelle Fajac, Jennifer L Taylor-Cousar, Marcus A Mall, Michael W Konstan, Nitin Nair, Jiaqiang Zhu, Emilio Arteaga-Solis, Fredrick Van Goor, Lisa McGarry, Valentin Prieto-Centurion, Patrick R Sosnay, Carmen Bozic, David Waltz, Nicole Mayer-Hamblett
Background: Highly effective CFTR modulators improve CFTR function and lead to dramatic improvements in health outcomes in many people with cystic fibrosis (pwCF). The relationship between measures of CFTR function, such as sweat chloride concentration, and clinical outcomes in pwCF treated with CFTR modulators is poorly defined. We conducted analyses to better understand the relationships between sweat chloride and CFTR function in vitro, and between sweat chloride and clinical outcomes following CFTR modulator treatment.
Methods: Mean sweat chloride values in healthy people, CF carriers, and pwCF treated with CFTR modulators at different doses were compared to chloride transport in corresponding human bronchial epithelial (HBE) cells. A pooled analysis of phase 3 CFTR modulator studies was performed to evaluate the relationship between attained values of sweat chloride and improvements in lung function, body mass index (BMI), patient reported outcomes, pulmonary exacerbations, and lung function change over time.
Results: Sweat chloride concentrations in vivo correlated strongly with CFTR-dependent chloride current in HBE cells in vitro. Sweat chloride values of <30 mmol/L and ≥30 to <60 mmol/L in pwCF following CFTR modulator treatment were associated with better clinical outcomes than sweat chloride ≥60 to <80 mmol/L and ≥80 mmol/L.
Conclusions: In pwCF treated with CFTR modulators, lower sweat chloride levels (reflecting greater CFTR function) are associated with better clinical outcomes. These results support the therapeutic strategy of further restoring CFTR function towards normal, as reflected in lowering sweat chloride to below the diagnostic threshold for CF (<60 mmol/L) and to normal (<30 mmol/L), with CFTR modulators.
{"title":"Sweat chloride reflects CFTR function and correlates with clinical outcomes following CFTR modulator treatment.","authors":"Edith T Zemanick, Bonnie Ramsey, Dorota Sands, Edward F McKone, Isabelle Fajac, Jennifer L Taylor-Cousar, Marcus A Mall, Michael W Konstan, Nitin Nair, Jiaqiang Zhu, Emilio Arteaga-Solis, Fredrick Van Goor, Lisa McGarry, Valentin Prieto-Centurion, Patrick R Sosnay, Carmen Bozic, David Waltz, Nicole Mayer-Hamblett","doi":"10.1016/j.jcf.2024.12.006","DOIUrl":"https://doi.org/10.1016/j.jcf.2024.12.006","url":null,"abstract":"<p><strong>Background: </strong>Highly effective CFTR modulators improve CFTR function and lead to dramatic improvements in health outcomes in many people with cystic fibrosis (pwCF). The relationship between measures of CFTR function, such as sweat chloride concentration, and clinical outcomes in pwCF treated with CFTR modulators is poorly defined. We conducted analyses to better understand the relationships between sweat chloride and CFTR function in vitro, and between sweat chloride and clinical outcomes following CFTR modulator treatment.</p><p><strong>Methods: </strong>Mean sweat chloride values in healthy people, CF carriers, and pwCF treated with CFTR modulators at different doses were compared to chloride transport in corresponding human bronchial epithelial (HBE) cells. A pooled analysis of phase 3 CFTR modulator studies was performed to evaluate the relationship between attained values of sweat chloride and improvements in lung function, body mass index (BMI), patient reported outcomes, pulmonary exacerbations, and lung function change over time.</p><p><strong>Results: </strong>Sweat chloride concentrations in vivo correlated strongly with CFTR-dependent chloride current in HBE cells in vitro. Sweat chloride values of <30 mmol/L and ≥30 to <60 mmol/L in pwCF following CFTR modulator treatment were associated with better clinical outcomes than sweat chloride ≥60 to <80 mmol/L and ≥80 mmol/L.</p><p><strong>Conclusions: </strong>In pwCF treated with CFTR modulators, lower sweat chloride levels (reflecting greater CFTR function) are associated with better clinical outcomes. These results support the therapeutic strategy of further restoring CFTR function towards normal, as reflected in lowering sweat chloride to below the diagnostic threshold for CF (<60 mmol/L) and to normal (<30 mmol/L), with CFTR modulators.</p>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142927282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-02DOI: 10.1016/j.jcf.2024.12.007
Grace M Rosner, Himanshu B Goswami, Katherine Sessions, Lindsay K Mendyka, Brenna Kerin, Irma Vlasac, Diane Mellinger, Lorraine Gwilt, Thomas H Hampton, Martha Graber, Alix Ashare, William T Harris, Brock Christensen, Bruce A Stanton, Agnieszka Swiatecka-Urban, Sladjana Skopelja-Gardner
Background: Adult people with cystic fibrosis (PwCF) have a higher risk of end-stage kidney disease than the general population. The nature and mechanism of kidney disease in CF are unknown. This study quantifies urinary kidney injury markers and examines the hypothesis that neutrophil activation and lung infection are associated with early kidney injury in CF.
Methods: Urinary total protein, albumin, and markers of kidney injury and neutrophil activation, normalized to creatinine, as well as urinary immune cells, were quantified in adult CF and healthy cohorts. Infection burden and chronicity were defined by sputum culture and serum titers of anti-bacterial antibodies.
Results: PwCF had increased urinary protein levels, consisting of low-molecular-weight tubular injury markers, independent of glomerular filtration rate (eGFR). This finding suggests subclinical renal injury processes. Urinary analysis of the CF cohort identified different associations of urinary injury markers with aminoglycoside exposure, lung function, and neutrophil activation. High urinary KIM-1 levels and increased prevalence of neutrophils among urine immune cells correlated with decreased lung function in PwCF. The relationship between tubular injury and reduced lung function was most prominent in patients harboring chronic Pseudomonas aeruginosa infection.
Conclusions: Increased urinary tubular injury markers in PwCF suggest early subclinical renal injury not readily detected by eGFR. The strong association of high urinary KIM-1 and neutrophils with diminished lung function and high Pseudomonas aeruginosa burden suggests that pulmonary disease may contribute to renal injury in CF.
{"title":"Lung-kidney axis in cystic fibrosis: Early urinary markers of kidney injury correlate with neutrophil activation and worse lung function.","authors":"Grace M Rosner, Himanshu B Goswami, Katherine Sessions, Lindsay K Mendyka, Brenna Kerin, Irma Vlasac, Diane Mellinger, Lorraine Gwilt, Thomas H Hampton, Martha Graber, Alix Ashare, William T Harris, Brock Christensen, Bruce A Stanton, Agnieszka Swiatecka-Urban, Sladjana Skopelja-Gardner","doi":"10.1016/j.jcf.2024.12.007","DOIUrl":"https://doi.org/10.1016/j.jcf.2024.12.007","url":null,"abstract":"<p><strong>Background: </strong>Adult people with cystic fibrosis (PwCF) have a higher risk of end-stage kidney disease than the general population. The nature and mechanism of kidney disease in CF are unknown. This study quantifies urinary kidney injury markers and examines the hypothesis that neutrophil activation and lung infection are associated with early kidney injury in CF.</p><p><strong>Methods: </strong>Urinary total protein, albumin, and markers of kidney injury and neutrophil activation, normalized to creatinine, as well as urinary immune cells, were quantified in adult CF and healthy cohorts. Infection burden and chronicity were defined by sputum culture and serum titers of anti-bacterial antibodies.</p><p><strong>Results: </strong>PwCF had increased urinary protein levels, consisting of low-molecular-weight tubular injury markers, independent of glomerular filtration rate (eGFR). This finding suggests subclinical renal injury processes. Urinary analysis of the CF cohort identified different associations of urinary injury markers with aminoglycoside exposure, lung function, and neutrophil activation. High urinary KIM-1 levels and increased prevalence of neutrophils among urine immune cells correlated with decreased lung function in PwCF. The relationship between tubular injury and reduced lung function was most prominent in patients harboring chronic Pseudomonas aeruginosa infection.</p><p><strong>Conclusions: </strong>Increased urinary tubular injury markers in PwCF suggest early subclinical renal injury not readily detected by eGFR. The strong association of high urinary KIM-1 and neutrophils with diminished lung function and high Pseudomonas aeruginosa burden suggests that pulmonary disease may contribute to renal injury in CF.</p>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142927254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.jcf.2024.09.005
Ondrej Cinek , Eva Furstova , Stepanka Novotna , Klara Hubackova , Tereza Dousova , Lucie Borek-Dohalska , Pavel Drevinek
The forskolin-induced swelling assay (FIS) in patient-derived intestinal organoids (PDIOs), used to determine in vitro responsiveness to elexacaftor/tezacaftor/ivacaftor (ETI), showed variability in swelling among PDIOs obtained from people with CF (pwCF) carrying the same F508del/F508del CFTR genotype. We aimed to characterise the effect of ETI on the transcriptional activity of PDIOs-derived cells to understand the intracellular processes triggered by ETI and the differences in treatment response. Six high- and six low-responding PDIOs to ETI, derived from F508del/F508del pwCF, were incubated with or without ETI for 2 to 6 h. Gene expression was assessed using 3′-mRNA sequencing and modelled using negative binomial models. Incubation with ETI resulted in a significant upregulation of several biological processes: mostly related to chemokines and signalling, chemotaxis, and tissue development processes. No changes were observed in abundance of the CFTR transcripts or in CFTR-related gene sets and pathways. The genes and pathways associated with ETI did not overlap with those whose expression changed with time only. PDIOs with a high FIS response did not significantly differ in any interpretable gene from the FIS-low organoids. The changes in the PDIOs gene expression upon the exposure to ETI cannot explain differences in the magnitude of PDIOs FIS-measured response to ETI. In conclusion, on incubation with ETI, genes of the CFTR-related pathways do not change their transcriptional activity; instead, overexpression was observed in genes of inflammatory-like cytokine response and receptor activation pathways.
用于确定体外对 elexacaftor/tezacaftor/ivacaftor (ETI) 反应性的患者衍生肠器官组织(PDIOs)中的福斯可林诱导肿胀试验(FIS)显示,从携带相同 F508del/F508del CFTR 基因型的 CF 患者(pwCF)中获得的 PDIOs 在肿胀方面存在差异。我们的目的是描述 ETI 对 PDIOs 派生细胞转录活性的影响,以了解 ETI 触发的细胞内过程以及治疗反应的差异。用 3'-mRNA 测序评估基因表达,并用负二项模型建模。与 ETI 一起孵育可显著上调多个生物过程:主要与趋化因子和信号传导、趋化和组织发育过程有关。在 CFTR 转录本的丰度或与 CFTR 相关的基因集和通路中未观察到任何变化。与 ETI 相关的基因和通路与仅随时间发生表达变化的基因和通路并不重叠。高 FIS 反应的 PDIO 与低 FIS 反应的有机体在任何可解释的基因上都没有显著差异。暴露于 ETI 时 PDIOs 基因表达的变化不能解释 PDIOs FIS 测定的对 ETI 反应程度的差异。总之,在与 ETI 培养时,CFTR 相关通路的基因并没有改变其转录活性;相反,在炎症类细胞因子反应和受体激活通路的基因中观察到了过表达。
{"title":"Gene expression profile of intestinal organoids from people with cystic fibrosis upon exposure to elexacaftor/tezacaftor/ivacaftor","authors":"Ondrej Cinek , Eva Furstova , Stepanka Novotna , Klara Hubackova , Tereza Dousova , Lucie Borek-Dohalska , Pavel Drevinek","doi":"10.1016/j.jcf.2024.09.005","DOIUrl":"10.1016/j.jcf.2024.09.005","url":null,"abstract":"<div><div>The forskolin-induced swelling assay (FIS) in patient-derived intestinal organoids (PDIOs), used to determine in vitro responsiveness to elexacaftor/tezacaftor/ivacaftor (ETI), showed variability in swelling among PDIOs obtained from people with CF (pwCF) carrying the same F508del/F508del <em>CFTR</em> genotype. We aimed to characterise the effect of ETI on the transcriptional activity of PDIOs-derived cells to understand the intracellular processes triggered by ETI and the differences in treatment response. Six high- and six low-responding PDIOs to ETI, derived from F508del/F508del pwCF, were incubated with or without ETI for 2 to 6 h. Gene expression was assessed using 3′-mRNA sequencing and modelled using negative binomial models. Incubation with ETI resulted in a significant upregulation of several biological processes: mostly related to chemokines and signalling, chemotaxis, and tissue development processes. No changes were observed in abundance of the <em>CFTR</em> transcripts or in <em>CFTR</em>-related gene sets and pathways. The genes and pathways associated with ETI did not overlap with those whose expression changed with time only. PDIOs with a high FIS response did not significantly differ in any interpretable gene from the FIS-low organoids. The changes in the PDIOs gene expression upon the exposure to ETI cannot explain differences in the magnitude of PDIOs FIS-measured response to ETI. In conclusion, on incubation with ETI, genes of the CFTR-related pathways do not change their transcriptional activity; instead, overexpression was observed in genes of inflammatory-like cytokine response and receptor activation pathways.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 1","pages":"Pages 157-163"},"PeriodicalIF":5.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142288300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.jcf.2024.09.023
Christina S. Thornton , Stephen E. Congly
{"title":"Regulatory delays in approval of CFTR modulating agents in Canada","authors":"Christina S. Thornton , Stephen E. Congly","doi":"10.1016/j.jcf.2024.09.023","DOIUrl":"10.1016/j.jcf.2024.09.023","url":null,"abstract":"","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 1","pages":"Pages 133-134"},"PeriodicalIF":5.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142347593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.jcf.2024.09.025
Theresa Jane Kolaczkowski , Amanda Bevan , Julian Legg , Jay Self , Mark Allenby
{"title":"Elevated liver function tests in infants exposed to elexacaftor-tezacaftor-ivacaftor in utero and while breastfeeding – Case reports","authors":"Theresa Jane Kolaczkowski , Amanda Bevan , Julian Legg , Jay Self , Mark Allenby","doi":"10.1016/j.jcf.2024.09.025","DOIUrl":"10.1016/j.jcf.2024.09.025","url":null,"abstract":"","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 1","pages":"Pages 16-18"},"PeriodicalIF":5.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142466565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}