Gen Comp Endocrinol. 2022 May 6:114051. doi: 10.1016/j.ygcen.2022.114051. Online ahead of print.

ABSTRACT

Prolactin (Prl) was identified over 60 years ago in mummichogs (Fundulus heteroclitus) as a "freshwater (FW)-adapting hormone", yet the cellular and molecular targets of Prl in this model teleost have remained unknown. Here, we conducted a phylogenetic analysis of two mummichog Prl receptors (Prlrs), designated Prlra and Prlrb, prior to describing the tissue- and salinity-dependent expression of their associated mRNAs. We then administered ovine Prl (oPrl) to mummichogs held in brackish water and characterized the expression of genes associated with FW- and seawater (SW)-type ionocytes. Within FW-type ionocytes, oPrl stimulated the expression of Na+/Cl- cotransporter 2 (ncc2) and aquaporin 3 (aqp3). Alternatively, branchial Na+/H+ exchanger 2 and -3 (nhe2 and -3) expression did not respond to oPrl. Gene transcripts associated with SW-type ionocytes, including Na+/K+/2Cl- cotransporter 1 (nkcc1), cystic fibrosis transmembrane regulator 1 (cftr1), and claudin 10f (cldn10f) were reduced by oPrl. Isolated gill filaments incubated with oPrl in vitro exhibited elevated ncc2 and prlra expression. Given the role of Aqps in supporting gastrointestinal fluid absorption, we assessed whether several intestinal aqp transcripts were responsive to oPrl and found that aqp1a and -8 levels were reduced by oPrl. Our collective data indicate that Prl promotes FW-acclimation in mummichogs by orchestrating the expression of solute transporters/channels, water channels, and tight-junction proteins across multiple osmoregulatory organs.

PMID:35533740 | DOI:10.1016/j.ygcen.2022.114051

Respir Med Res. 2021 Dec 17;81:100866. doi: 10.1016/j.resmer.2021.100866. Online ahead of print.

NO ABSTRACT

PMID:35533474 | DOI:10.1016/j.resmer.2021.100866

Ann Am Thorac Soc. 2022 May 9. doi: 10.1513/AnnalsATS.202111-1257OC. Online ahead of print.

ABSTRACT

RATIONALE: It remains unclear whether bronchiectasis increases the risk of lung cancer, because smoking history was not considered in previous studies.

OBJECTIVES: To evaluate whether participants with bronchiectasis have a higher risk of incident lung cancer than those without bronchiectasis with information on smoking status.

METHODS: This was a population-based cohort study of 3,858,422 individuals who participated in the 2009 National Health Screening Program. We evaluated the incidence of lung cancer in participants with bronchiectasis (n = 65,305) and those without bronchiectasis (n = 3,793,117). We followed the cohort was up until the date of lung cancer diagnosis, date of death, or December 2018. Cox proportional hazard regression models were used to evaluate the relative risk of lung cancer between participants with bronchiectasis and those without bronchiectasis.

RESULTS: The incidence of lung cancer in participants with bronchiectasis was significantly higher than in those without bronchiectasis (2.099 vs. 0.742 per 1,000 person-years, P < 0.001), with an adjusted hazard ratio (aHR) of 1.22 (95% confidence interval [CI]=1.14-1.30) in the model adjusting for potential confounders and accounting for the competing risk of mortality. Regardless of smoking status, the risk of lung cancer was significantly higher in participants with bronchiectasis than in those without bronchiectasis (aHR = 1.28, 95% CI = 1.17-1.41 for never smokers; aHR = 1.26, 95% CI = 1.10-1.44 for ever smokers). Although bronchiectasis did not increase the risk of lung cancer among participants with COPD, it significantly increased the risk of lung cancer in non-COPD participants (aHR = 1.19, 95% CI = 1.09-1.31).

CONCLUSION: The presence of bronchiectasis was associated with a higher risk of lung cancer after considering the smoking status.

PMID:35533306 | DOI:10.1513/AnnalsATS.202111-1257OC

J Vis Exp. 2022 Apr 22;(182). doi: 10.3791/63409.

ABSTRACT

Human nasal epithelial (HNE) cells are easy to collect by simple, non-invasive nasal brushing. Patient-derived primary HNE cells can be amplified and differentiated into a pseudo-stratified epithelium in air-liquid interface conditions to quantify cyclic AMP-mediated Chloride (Cl-) transport as an index of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) function. If critical steps such as quality of nasal brushing and cell density upon cryopreservation are performed efficiently, HNE cells can be successfully biobanked. Moreover, short-circuit current studies demonstrate that freeze-thawing does not significantly modify HNE cells' electrophysiological properties and response to CFTR modulators. In the culture conditions used in this study, when less than 2 x 106 cells are frozen per cryovial, the failure rate is very high. We recommend freezing at least 3 x 106 cells per cryovial. We show that dual therapies combining a CFTR corrector with a CFTR potentiator have a comparable correction efficacy for CFTR activity in F508del-homozygous HNE cells. Triple therapy VX-445 + VX-661 + VX-770 significantly increased correction of CFTR activity compared to dual therapy VX-809 + VX-770. The measure of CFTR activity in HNE cells is a promising pre-clinical biomarker useful to guide CFTR modulator therapy.

PMID:35532277 | DOI:10.3791/63409

J Vis Exp. 2022 Apr 21;(182). doi: 10.3791/63876.

ABSTRACT

In muco-obstructive lung diseases (e.g., asthma, chronic obstructive pulmonary disease, cystic fibrosis) and other respiratory conditions (e.g., viral/bacterial infections), mucus biophysical properties are altered by goblet cell hypersecretion, airway dehydration, oxidative stress, and the presence of extracellular DNA. Previous studies showed that sputum viscoelasticity correlated with pulmonary function and that treatments affecting sputum rheology (e.g., mucolytics) can result in remarkable clinical benefits. In general, rheological measurements of non-Newtonian fluids employ elaborate, time-consuming approaches (e.g., parallel/cone-plate rheometers and/or microbead particle tracking) that require extensive training to perform the assay and interpret the data. This study tested the reliability, reproducibility, and sensitivity of Rheomuco, a user-friendly benchtop device that is designed to perform rapid measurements using dynamic oscillation with a shear-strain sweep to provide linear viscoelastic moduli (G', G", G*, and tan δ) and gel point characteristics (γc and σc) for clinical samples within 5 min. Device performance was validated using different concentrations of a mucus simulant, 8 MDa polyethylene oxide (PEO), and against traditional bulk rheology measurements. A clinical isolate harvested from an intubated patient with status asthmaticus (SA) was then assessed in triplicate measurements and the coefficient of variation between measurements is <10%. Ex vivo use of a potent mucus reducing agent, TCEP, on SA mucus resulted in a five-fold decrease in elastic modulus and a change toward a more "liquid-like" behavior overall (e.g., higher tan δ). Together, these results demonstrate that the tested benchtop rheometer can make reliable measures of mucus viscoelasticity in clinical and research settings. In summary, the described protocol could be used to explore the effects of mucoactive drugs (e.g., rhDNase, N-acetyl cysteine) onsite to adapt treatment on a case-by-case basis, or in preclinical studies of novel compounds.

PMID:35532240 | DOI:10.3791/63876

Biol Reprod. 2022 May 9:ioac090. doi: 10.1093/biolre/ioac090. Online ahead of print.

ABSTRACT

The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) is an apical membrane chloride/bicarbonate ion channel in epithelial cells. Mutations in CFTR cause cystic fibrosis (CF), a disease characterized by thickened mucus secretions and is associated with subfertility and infertility. CFTR function has been well characterized in vitro and in vivo in airway and other epithelia studies. However, little is known about CFTR function in the cervix in health and its contribution to cyclic regulation of fertility from endocervical mucus changes. Contributing to this research gap is the lack of information on effect of sex steroid hormones on CFTR expression in cervix epithelial cells across the menstrual cycle. Herein we demonstrate hormonal regulation of CFTR expression in endocervical cells both in vitro and in vivo, and that conditionally reprogrammed endocervical epithelial cells can be used to interrogate CFTR ion channel function. CFTR activity was demonstrated in vitro using electrophysiology methods and functionally inhibited with the CFTR-specific inhibitors inh-172 and GlyH-101. We also report that CFTR expression is increased by estradiol in the macaque cervix both in vitro and in vivo in Rhesus macaques treated with artificial menstrual cycles. Estrogen upregulation of CFTR is blocked in vivo by co-treatment with progesterone. Our findings provide the most comprehensive evidence to date that steroid hormones drive changes in CFTR expression. These data are integral to understanding the role of CFTR as a fertility regulator in the endocervix. Summary: CFTR is hormonally regulated and functional in the macaque endocervix.

PMID:35532160 | DOI:10.1093/biolre/ioac090

Front Chem. 2022 Apr 21;10:782608. doi: 10.3389/fchem.2022.782608. eCollection 2022.

ABSTRACT

The trypsin-like proteases (TLPs) play widespread and diverse roles, in a host of physiological and pathological processes including clot dissolution, extracellular matrix remodelling, infection, angiogenesis, wound healing and tumour invasion/metastasis. Moreover, these enzymes are involved in the disruption of normal lung function in a range of respiratory diseases including allergic asthma where several allergenic proteases have been identified. Here, we report the synthesis of a series of peptide derivatives containing an N-alkyl glycine analogue of arginine, bearing differing electrophilic leaving groups (carbamate and triazole urea), and demonstrate their function as potent, irreversible inhibitors of trypsin and TLPs, to include activities from cockroach extract. As such, these inhibitors are suitable for use as activity probes (APs) in activity-based profiling (ABP) applications.

PMID:35529696 | PMC:PMC9068901 | DOI:10.3389/fchem.2022.782608

Front Pediatr. 2022 Apr 21;10:852551. doi: 10.3389/fped.2022.852551. eCollection 2022.

ABSTRACT

BACKGROUND: The effect of elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) on glucose tolerance and/or cystic-fibrosis-related diabetes (CFRD) is not well understood. We performed an observational study on the short-term effects of ELX/TEZ/IVA on glucose tolerance.

METHODS: Sixteen adolescents with CF performed oral glucose tolerance tests (OGTT) before and 4-6 weeks after initiating ELX/TEZ/IVA therapy. A continuous glucose monitoring (CGM) system was used 3 days before until 7 days after starting ELX/TEZ/IVA treatment.

RESULTS: OGTT categories improved after initiating ELX/TEZ/IVA therapy (p = 0.02). Glucose levels of OGTT improved at 60, 90, and 120 min (p < 0.05), whereas fasting glucose and CGM measures did not change.

CONCLUSION: Shortly after initiating ELX/TEZ/IVA therapy, glucose tolerance measured by OGTT improved in people with CF. This pilot study indicates that ELX/TEZ/IVA treatment has beneficial effects on the endocrine pancreatic function and might prevent or at least postpone future CFRD.

PMID:35529332 | PMC:PMC9070552 | DOI:10.3389/fped.2022.852551

Biomed Res Int. 2022 Apr 29;2022:8078259. doi: 10.1155/2022/8078259. eCollection 2022.

ABSTRACT

Coronaviruses are a family of viruses that infect mammals and birds. Coronaviruses cause infections of the respiratory system in humans, which can be minor or fatal. A comparative transcriptomic analysis has been performed to establish essential profiles of the gene expression of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) linked to cystic fibrosis (CF). Transcriptomic studies have been carried out in relation to SARS-CoV-2 since a number of people have been diagnosed with CF. The recognition of differentially expressed genes demonstrated 8 concordant genes shared between the SARS-CoV-2 and CF. Extensive gene ontology analysis and the discovery of pathway enrichment demonstrated SARS-CoV-2 response to CF. The gene ontological terms and pathway enrichment mechanisms derived from this research may affect the production of successful drugs, especially for the people with the following disorder. Identification of TF-miRNA association network reveals the interconnection between TF genes and miRNAs, which may be effective to reveal the other influenced disease that occurs for SARS-CoV-2 to CF. The enrichment of pathways reveals SARS-CoV-2-associated CF mostly engaged with the type of innate immune system, Toll-like receptor signaling pathway, pantothenate and CoA biosynthesis, allograft rejection, graft-versus-host disease, intestinal immune network for IgA production, mineral absorption, autoimmune thyroid disease, legionellosis, viral myocarditis, inflammatory bowel disease (IBD), etc. The drug compound identification demonstrates that the drug targets of IMIQUIMOD and raloxifene are the most significant with the significant hub DEGs.

PMID:35528173 | PMC:PMC9076317 | DOI:10.1155/2022/8078259

Paediatr Anaesth. 2022 May 8. doi: 10.1111/pan.14462. Online ahead of print.

NO ABSTRACT

PMID:35527234 | DOI:10.1111/pan.14462

J Cyst Fibros. 2022 May 5:S1569-1993(22)00108-4. doi: 10.1016/j.jcf.2022.04.019. Online ahead of print.

ABSTRACT

In December 2020, the U.S. Food and Drug Administration (FDA) expanded the list of CFTR variants approved for treatment with CFTR modulators drugs from 39 to 183. Clinicians should be aware that individuals harboring certain variants approved for treatment may not respond to or benefit from this therapy. After review, the expert panel leading the CFTR2 project identified four categories of variants that may not result in a clinical response to modulator treatment: 15 variants assigned as non CF-causing; 45 variants of unknown significance; six variants known or suspected to cause mis-splicing as their primary defect rather than an amino acid substitution; and eight variants known to occur together in cis with another deleterious variant not expected to lead to CFTR protein (nonsense or frameshift). The potential risks and benefits of CFTR modulator therapy should be considered carefully for individuals harboring these variants.

PMID:35527187 | DOI:10.1016/j.jcf.2022.04.019

Actas Dermosifiliogr. 2022 Mar;113(3):T254-T260. doi: 10.1016/j.ad.2022.02.003. Epub 2022 Feb 10.

ABSTRACT

Aquagenic keratoderma is an uncommon acquired dermatosis characterized by edema and whitish-translucent papules triggered by immersion or contact with water. Cases have been described in association with certain medications, hyperhidrosis, and cystic fibrosis. The aim of this review is to evaluate the effectiveness of different treatments for aquagenic keratoderma. We reviewed the literature and analyzed treatments for aquagenic keratoderma described in case series and reports. Aquagenic keratoderma associated with hyperhidrosis can be treated effectively. Tap water iontophoresis, endoscopic thoracic sympathectomy, botulinum toxin injections, and oxybutynin are effective against refractory forms. Topical salicylic acid and aluminum salts are effective, but of little value as maintenance therapy. Oral oxybutynin 5mg/d is probably the best option for treating aquagenic keratoderma. The reported pathophysiological effects of nonsteroidal anti inflammatory drugs in this setting suggest that the use of prostaglandins might be justified. Additional studies are needed to investigate these hypotheses and resolve other questions.

PMID:35526934 | DOI:10.1016/j.ad.2022.02.003

Chest. 2022 May;161(5):e332-e333. doi: 10.1016/j.chest.2021.12.641.

NO ABSTRACT

PMID:35526914 | DOI:10.1016/j.chest.2021.12.641

Chest. 2022 May;161(5):e325-e326. doi: 10.1016/j.chest.2022.01.055.

NO ABSTRACT

PMID:35526906 | DOI:10.1016/j.chest.2022.01.055

Respir Med Res. 2022 Feb 26;81:100896. doi: 10.1016/j.resmer.2022.100896. Online ahead of print.

ABSTRACT

BACKGROUND: Patient-important outcomes (PIOs) have emerged in respiratory medicine, in order to place the patient at the center of research. Mortality is a debated PIO in lung transplantation (LTx). The use of PIO in this specific setting has never been studied. We aimed to systematically review the use of PIOs in LTx research.

METHODS: MEDLINE, Cochrane Library and Embase databases were searched to include prospective studies published in 2019, involving adult LTx recipients. We excluded articles reporting non-prognostic studies, letters, reviews, commentaries, or case reports. PIOs considered were mortality, pain, physical function, pulmonary, gastrointestinal, neuropsychological, cardiac, sleep or sexual symptoms and quality of life. This systematic review was prospectively registered in the PROSPERO register (CRD42020163425).

RESULTS: Among 1048 references retrieved, 51 were finally included in the analysis. In total, 26 (51%) studies investigated at least one PIO, as a primary outcome in 12 (23.5%) and secondary outcome in 21 (41.2%). In 15 (29.4%) studies, mortality was the most frequently reported PIO; 11 (21.5%) studies evaluated at least one PIO other than mortality, quality of life being this PIO in 6.

CONCLUSIONS: PIOs were described in half of prospective articles dealing with adult LTx recipients published in 2019. Outcomes other than mortality were insufficiently considered. A core outcome set of PIOs in LTx should be developed with patient input to guide future research in LTx.

PMID:35526317 | DOI:10.1016/j.resmer.2022.100896

Int J Pharm. 2022 May 4:121799. doi: 10.1016/j.ijpharm.2022.121799. Online ahead of print.

ABSTRACT

Pseudomonas aeruginosa infection is common in cystic fibrosis as well non-cystic fibrosis bronchiectasis. The pathogen presents challenges for treatment due to its adaptive antibiotic-resistance, mainly pertaining to its biofilm-forming ability, as well as limitations associated with conventional drug delivery in achieving desired therapeutic concentration in the infection site. Hence, therapeutic approach has shifted towards the inhalation of antibiotics. Ceftazidime is a potent antibiotic against the pathogen; however, it is currently only available as a parenteral formulation. Here, spray-dryer was employed to generate inhalable high dose ceftazidime microparticles. In addition, the use of amino acids (valine, leucine, methionine, phenylalanine, and tryptophan) to improve aerosolization as well as chemical stability of amorphous ceftazidime was explored. The particles were characterized using X ray diffraction, infrared (IR) spectroscopy, calorimetry, electron microscopy, particle size analyzer, and next generation impactor. The chemical stability at 25 °C/<15% was assessed using chromatography. All co-spray dried formulations were confirmed as monophasic amorphous systems using calorimetry. In addition, principal component analysis of the IR spectra suggested potential interaction between tryptophan and ceftazidime in the co-amorphous matrix. Inclusion of amino acids improved aerosolization and chemical stability in all cases. Increase in surface asperity was clear with the use of amino acids which likely contributed to the improved aerosol performance, and potential interaction between amino acids and ceftazidime was plausibly the reason for improved chemical stability. Leucine offered the best aerosolization enhancement with a fine particle fraction of 78% and tryptophan showed stabilizing superiority by reducing chemical degradation by 51% over 10 weeks in 1:1 molar ratio. The protection against ceftazidime degradation varied with the nature of amino acids. Additionally, there was a linear relationship between degradation protection and molar mass of amino acids or percentage weight of amino acids in the formulations. None of the amino acids were successful in completely inhibiting degradation of ceftazidime in amorphous spray-dried powder to prepare a commercially viable product with desired shelf-life. All the amino acids and ceftazidime were non-toxic to A549 alveolar cell line.

PMID:35525472 | DOI:10.1016/j.ijpharm.2022.121799

Orphanet J Rare Dis. 2022 May 7;17(1):188. doi: 10.1186/s13023-022-02350-5.

ABSTRACT

BACKGROUND: Over the past decade, a new class of drugs called CFTR (cystic fibrosis transmembrane conductance regulator) modulators have shown to be able to improve clinical outcomes in patient with Cystic Fibrosis. In this analysis, we have extensively reviewed the regulatory pathways and decisions adopted by FDA and EMA to speed up the development, the review and the approval of these drugs, with the aim of identifying possible clinical and public health implications associated with differences.

RESULTS: CFTR modulators have been developed towards addressing three main genetic domains: (1) F508del homozygous (F508del/F508del), (2) F508del heterozygous, and (3) genotypes not carrying F508del mutation; and expanded from adult to paediatric population. Programs to expedite the reviewing and licensing of CFTR modulators were extensively adopted by FDA and EMA. All CFTR modulators have been licensed in the US as orphan drugs, but in the EU the orphan status for LUM/IVA was not confirmed at the time of marketing authorization as results from the pivotal trial were not considered clinically significant. While FDA and EMA approved CFTR modulators on the basis of results from phase III double-blind RCTs, main differences were found on the extension of indications: FDA accepted non-clinical evidence considering a recovery of the CFTR function ≥ 10% based on chloride transport, a reliable indicator to correlate with improvement in clinical outcomes. By contrast, EMA did not deem preclinical data sufficient to expand the label of CFTR modulators without confirmatory clinical data.

CONCLUSIONS: Regulators played an important role in fostering the development and approval of CFTR modulators. However, differences were found between FDA and EMA in the way of reviewing and licensing CFTR modulators, which extended beyond semantics affecting patients' eligibility and access: FDA's approach was more mechanistic/biology-driven while the EMA's one was more oriented by clinical evidence. This might refer to the connection between the EMA and the Member States, which tends to base decisions on pricing and reimbursement on clinical data rather than pre-clinical ones. Here we have proposed a two-step personalized-based model to merge the ethical commitment of ensuring larger access to all potential eligible patients (including those harboring very rare mutations) with the one of ensuring access to clinically assessed and effective medicines through Real World Data.

PMID:35525974 | DOI:10.1186/s13023-022-02350-5

BMC Pulm Med. 2022 May 7;22(1):183. doi: 10.1186/s12890-022-01977-1.

ABSTRACT

BACKGROUND: Transforming Growth Factor-β1 (TGF-β1) is a genetic modifier in patients with cystic fibrosis (CF). Several single nucleotide polymorphisms (SNPs) of TGF-β1 are associated with neutrophilic inflammation, lung fibrosis and loss of pulmonary function.

AIM: The aim of this study was to assess the relationship between genetic TGF-β1 polymorphisms and pulmonary disease progression in CF patients. Furthermore, the effect of TGF-β1 polymorphisms on inflammatory cytokines in sputum was investigated.

METHODS: 56 CF-patients and 62 controls were genotyped for three relevant SNPs in their TGF-β1 sequence using the SNaPshot® technique. Individual "slopes" in forced expiratory volume in 1 s (FEV1) for all patients were calculated by using documented lung function values of the previous five years. The status of Pseudomonas aeruginosa (Pa) infection was determined. Sputum concentrations of the protease elastase, the serine protease inhibitor elafin and the cytokines IL-1β, IL-8, IL-6, TNF-α were measured after a standardized sputum induction and processing.

RESULTS: The homozygous TT genotype at codon 10 was associated with a lower rate of chronic Pa infection (p < 0.05). The heterozygous GC genotype at codon 25 was associated with lower lung function decline (p < 0.05). Patients with homozygous TT genotype at the promotor SNP showed higher levels of TNF-α (p < 0,05). Higher levels of TGF-β1 in plasma were associated with a more rapid FEV1 decline over five years (p < 0.05).

CONCLUSIONS: Our results suggest that polymorphisms in the TGF-β1 gene have an effect on lung function decline, Pa infection as well as levels of inflammatory cytokines. Genotyping these polymorphisms could potentially be used to identify CF patients with higher risk of disease progression. TGF-β1 inhibition could potentially be developed as a new therapeutic option to modulate CF lung disease.

PMID:35525938 | DOI:10.1186/s12890-022-01977-1

J Cyst Fibros. 2022 May 4:S1569-1993(22)00106-0. doi: 10.1016/j.jcf.2022.04.016. Online ahead of print.

ABSTRACT

BACKGROUND: Manifestations of cystic fibrosis, although well-characterized in the proximal airways, are understudied in the distal lung. Characterization of the cystic fibrosis lung 'matrisome' (matrix proteome) has not been previously described, and could help identify biomarkers and inform therapeutic strategies.

METHODS: We performed liquid chromatography-mass spectrometry, gene ontology analysis, and multi-modal imaging, including histology, immunofluorescence, and electron microscopy for a comprehensive evaluation of distal human lung extracellular matrix (matrix) structure and composition in end-stage cystic fibrosis.

RESULTS: Quantitative proteomic profiling identified sixty-eight (68) matrix constituents with significantly altered expression in end-stage cystic fibrosis. Over 90% of significantly different matrix peptides detected, including structural and basement membrane proteins, were expressed at lower levels in cystic fibrosis. However, the total abundance of matrix in cystic fibrosis lungs was not significantly different from control lungs, suggesting that cystic fibrosis leads to loss of diversity among lung matrix proteins rather than an absolute loss of matrix. Visualization of distal lung matrix via immunofluorescence and electron microscopy revealed pathological remodeling of distal lung tissue architecture and loss of alveolar basement membrane, consistent with significantly altered pathways identified by gene ontology analysis.

CONCLUSIONS: Dysregulation of matrix organization and aberrant wound healing pathways are associated with loss of matrix protein diversity and obliteration of distal lung tissue structure in end-stage cystic fibrosis. While many therapeutics aim to functionally restore defective cystic fibrosis transmembrane conductance regulator (CFTR), drugs that target dysregulated matrix pathways may serve as adjunct interventions to support lung recovery.

PMID:35525782 | DOI:10.1016/j.jcf.2022.04.016

Am J Kidney Dis. 2022 May 4:S0272-6386(22)00516-9. doi: 10.1053/j.ajkd.2021.12.016. Online ahead of print.

ABSTRACT

Metabolic alkalosis is a widespread acid-base disturbance, especially in hospitalized patients. It is characterized by the primary elevation of serum bicarbonate and arterial pH, along with a compensatory increase in Pco2 consequent to adaptive hypoventilation. The pathogenesis of metabolic alkalosis involves either a loss of fixed acid or a net accumulation of bicarbonate within the extracellular fluid. The loss of acid may be via the gastrointestinal tract or the kidney, whereas the sources of excess alkali may be via oral or parenteral alkali intake. Severe metabolic alkalosis in critically ill patients-arterial blood pH of 7.55 or higher-is associated with significantly increased mortality rate. The kidney is equipped with sophisticated mechanisms to avert the generation or the persistence (maintenance) of metabolic alkalosis by enhancing bicarbonate excretion. These mechanisms include increased filtration as well as decreased absorption and enhanced secretion of bicarbonate by specialized transporters in specific nephron segments. Factors that interfere with these mechanisms will impair the ability of the kidney to eliminate excess bicarbonate, therefore promoting the generation or impairing the correction of metabolic alkalosis. These factors include volume contraction, low glomerular filtration rate, potassium deficiency, hypochloremia, aldosterone excess, and elevated arterial carbon dioxide. Major clinical states are associated with metabolic alkalosis, including vomiting, aldosterone or cortisol excess, licorice ingestion, chloruretic diuretics, excess calcium alkali ingestion, and genetic diseases such as Bartter syndrome, Gitelman syndrome, and cystic fibrosis. In this installment in the AJKD Core Curriculum in Nephrology, we will review the pathogenesis of metabolic alkalosis; appraise the precipitating events; and discuss clinical presentations, diagnoses, and treatments of metabolic alkalosis.

PMID:35525634 | DOI:10.1053/j.ajkd.2021.12.016