{"doi":"10.1165/rcmb.2024-0326ed","title":"The Hidden Link between Chronic Kidney Disease and Lung Injury","abstract":"The Hidden Link between Chronic Kidney Disease and Lung Injury Chronic kidney disease (CKD), a progressive condition affecting millions globally, is characterized by the irreversible loss of kidney function.This results in a decreased ability to excrete phosphate, leading to hyperphosphatemia, a condition marked by systemically elevated phosphate concentrations in the blood (1).Hyperphosphatemia is associated with increased inflammation and cardiovascular and pulmonary diseases, including fibrotic interstitial lung diseases (2).Historically, however, the focus of CKD management has been on restoring kidney function and on the involvement of the cardiovascular system, often overlooking the involvement of the respiratory system (3, 4).Clinical studies in patients with CKD have increasingly reported higher incidences of restrictive lung diseases, including idiopathic pulmonary fibrosis (IPF) (5, 6), indicating a need for further investigation into the kidney-lung axis.In this issue of the Journal, Bollenbecker and colleagues (pp.659-676) hypothesize that CKD-driven hyperphosphatemia is sufficient to induce lung injury and fibrosis (7).Using a mouse model of CKD that uses an adenine-rich diet to simulate hyperphosphatemia, the authors observed that these mice developed inflammation and subsequent lung fibrosis, suggesting a direct link between high phosphate concentrations and lung injury.In addition, administration of a high-phosphate diet followed by bleomycin treatment exacerbated lung inflammation at Day 17 and fibrosis by Day 21, even in the absence of kidney damage (7).The authors show that a high concentration of phosphate itself is a critical mediator of lung injury, independent of other CKD-related factors, through activation of ERK 1/2 (extracellular signal related kinase 1/2) and PKB/AKT (protein kinase B) signaling ( 7).As a whole, their findings represent a paradigm shift in our understanding of the pulmonary effects of elevated systemic phosphate associated with CKD.By linking hyperphosphatemia to lung fibrosis through the MAPK (mitogen-activated protein kinases)/AKT signaling pathway, the study not only broadens the scope of CKD research but also offers hope for new cross-organ therapeutic strategies.The PI3K (phosphatidylinositol 3-kinase)/AKT signaling pathway is vital in regulating cell growth, motility, metabolism, and survival.Class I PI3Ks, including PI3Kg, are involved in lung diseases, with PI3Kg overexpression and increased activation seen in IPF tissue (8, 9).AKT1/2 activation by PI3K has been shown to play multiple roles in pulmonary fibrosis.AKT1-mediated mitophagy was required for fibrosis development by increasing the apoptosis resistance of alveolar macrophages (10), and AKT2-deficient mice were protected from bleomycin-induced fibrosis (11).Injured alveolar epithelial cells activate the PI3K/AKT pathway, releasing TGF-b and inducing fibroblast proliferation, differentiation, extracellular matrix remodeling, and activation of downstream pathways, including mTOR, HIF-1a, and FOX family proteins","journal":"American Journal of Respiratory Cell and Molecular Biology","year":2024,"id":502042,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9607,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":311984,"name":"Elizabeth F. Redente","orcid":"0000-0002-8075-4325","position":0,"is_corresponding":true}],"reference_count":26,"raw_metadata":null,"created_at":"2026-07-19T02:10:19.647285Z","pmid":"39137327","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}