The Journal of clinical endocrinology and metabolism · 2025
Progressive 11β-Hydroxysteroid Dehydrogenase Type 2 Insufficiency as Kidney Function Declines.
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Uslar Thomas, Newman Andrew J, Tapia-Castillo Alejandra, Carvajal Cristian A, Fardella Carlos E, Allende Fidel, Solari Sandra, Tsai Laura C, Milks Julia, Cherney Michael, Stouffer David G, Auchus Richard, Brown Jenifer M, Baudrand René, Vaidya Anand
Аннотация
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.
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.