Browsing by Author "Milks, Julia"

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    Progressive 11β-hydroxysteroid dehydrogenase type 2 insufficiency as kidney function declines
    (2024) Uslar N., Thomas; Newman, Andrew J.; Tapia Castillo, Alejandra; Carvajal Maldonado, Cristián Andrés; Fardella B., Carlos; Allende, Fidel; Solari, Sandra; Tsai, Laura C.; Milks, Julia; Cherney, Michael; Stouffer, David G.; Auchus, Richard; Brown, Jenifer M.; Baudrand Biggs, René; Vaidya, Anand
    Background It has been postulated that chronic kidney disease (CKD) is a state of relative 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta HSD2) insufficiency, resulting in increased cortisol-mediated mineralocorticoid receptor (MR) activation. We hypothesized that relative 11 beta HSD2 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 11 beta HSD2 activity. A validation cohort (n = 101) enrolled only individuals with normal kidney function (eGFR >= 60 mL/min/1.73 m(2)) in whom 11 beta HSD2 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 11 beta HSD2 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.