{"doi":"10.1210/clinem/dgae663","title":"Progressive 11β-Hydroxysteroid Dehydrogenase Type 2 Insufficiency as Kidney Function Declines","abstract":"BACKGROUND: It has been postulated that chronic kidney disease (CKD) is a state of relative 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) insufficiency, resulting in increased cortisol-mediated mineralocorticoid receptor (MR) activation. We hypothesized that relative 11βHSD2 insufficiency manifests across a wide spectrum of progressively declining kidney function, including within the normal range. METHODS: Adult participants were recruited at 2 academic centers. A discovery cohort (n = 500) enrolled individuals with estimated glomerular filtration rate (eGFR) ranging from normal to CKD stage 5, in whom serum cortisol-to-cortisone (F/E) was measured as a biomarker of 11βHSD2 activity. A validation cohort (n = 101) enrolled only individuals with normal kidney function (eGFR ≥ 60 mL/min/1.73 m2) in whom 11βHSD2 activity was assessed via serum F/E and 11-hydroxy-to-11-keto androgen (11OH/K) ratios following multiple maneuvers: oral sodium suppression test, dexamethasone suppression test (DST), and ACTH-stimulation test (ACTHstim). RESULTS: In the discovery cohort, lower eGFR was associated with higher F/E (P-trend < .001). Similarly, in the validation cohort, with normal eGFR, an inverse association between eGFR and both F/E and 11OH/K ratios was observed (P-trend < .01), which persisted following DST (P-trend < .001) and ACTHstim (P-trend < .05). The fractional excretion of potassium, a marker of renal MR activity, was higher with higher F/E (P-trend < .01) and with lower eGFR (P-trend < .0001). CONCLUSION: A continuum of declining 11βHSD2 activity was observed with progressively lower eGFR in individuals spanning a wide spectrum of kidney function, including those with apparently normal kidney function. These findings implicate cortisol-mediated MR activation in the pathophysiology of hypertension and cardiovascular disease in CKD.","journal":"The Journal of Clinical Endocrinology & Metabolism","year":2024,"id":427923,"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":14,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9384,"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":729665,"name":"Andrew J Newman","orcid":"0000-0002-8326-1964","position":1,"is_corresponding":false},{"id":1228627,"name":"Alejandra Tapia-Castillo","orcid":"0000-0002-6081-1468","position":2,"is_corresponding":false},{"id":733534,"name":"Cristián A. Carvajal","orcid":"0000-0002-0668-412X","position":3,"is_corresponding":false},{"id":1228628,"name":"Carlos Fardella","orcid":"0000-0002-5500-4434","position":4,"is_corresponding":false},{"id":1228629,"name":"Fidel Allende","orcid":"0000-0002-6508-4052","position":5,"is_corresponding":false},{"id":1229087,"name":"Sandra Solari","orcid":null,"position":6,"is_corresponding":false},{"id":1205369,"name":"Laura C Tsai","orcid":"0009-0008-5344-2589","position":7,"is_corresponding":false},{"id":1206231,"name":"Julia Milks","orcid":null,"position":8,"is_corresponding":false},{"id":1228630,"name":"Michael D. Cherney","orcid":"0000-0001-8422-5319","position":9,"is_corresponding":false},{"id":723165,"name":"David G. Stouffer","orcid":"0009-0008-9453-8819","position":10,"is_corresponding":false},{"id":369854,"name":"Richard J. Auchus","orcid":"0000-0001-6815-6181","position":11,"is_corresponding":false},{"id":301182,"name":"Jenifer M. Brown","orcid":"0000-0002-6647-639X","position":12,"is_corresponding":false},{"id":419658,"name":"René Baudrand","orcid":"0000-0002-8655-4957","position":13,"is_corresponding":false},{"id":263020,"name":"Anand Vaidya","orcid":"0000-0002-0314-9252","position":14,"is_corresponding":false},{"id":927482,"name":"Thomas Uslar","orcid":"0000-0001-7213-855X","position":0,"is_corresponding":true}],"reference_count":35,"raw_metadata":null,"created_at":"2026-07-19T01:58:52.576447Z","pmid":"39312227","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":[]}