OR19-04 Progressive 11-beta-HSD2 Insufficiency and Mineralocorticoid Receptor Activation as Kidney Function Declines

Abstract A.J. Newman: None. T. Uslar: None. A. Tapia: None. C.A. Carvajal: None. C.E. Fardella: None. F. Allende: None. S. Solari: None. L.C. Tsai: None. J. Milks: None. M.D. Cherney: None. D. Stouffer: None. R.J. Auchus: None. J.M. Brown: None. R. Baudrand: None. A. Vaidya: None. Background: The ratio of plasma cortisol-to-cortisone (F/E) is a biomarker of 11βHSD2 activity. It has been postulated that progressive chronic kidney disease (CKD) results in relative 11βHSD2 insufficiency, and thereby a higher F/E, and hence a state of increased cortisol-mediated mineralocorticoid receptor (MR) activation. We postulated that relative 11βHSD2 insufficiency might manifest across a wide spectrum of kidney function, including within the normal range. Methods: Adult participants were prospectively recruited from two academic centers. The exploratory cohort (n=245) enrolled individuals with normal estimated glomerular filtration (eGFR) as well as those with stage 3 and 4 CKD (eGFR range ≥ 15 mL/min/1.73 m2). The validation cohort (n=101) enrolled only individuals with normal kidney function (eGFR range ≥ 60 mL/min/1.73 m2). Participants from both centers underwent circulating adrenal steroid profiling via LC-MS/MS in a seated position. In addition, participants from the validation cohort had adrenal steroids measured following an overnight dexamethasone suppression test (DST) and cosyntropin stimulation test (CST). Linear regression was used to assess trends across quartiles of eGFR. Results: In the exploratory cohort, as eGFR declined, F/E was significantly higher (P-trend <0.001) and serum potassium was significantly lower (P-trend=0.003). In the validation cohort with normal eGFR, an inverse association between F/E and eGFR was again observed (P-trend < 0.01) and persisted following DST (P-trend < 0.001) and CST (P-trend < 0.05). Potassium homeostasis again reflected a pattern of greater MR activation as eGFR declined: 24h urinary potassium excretion (P-trend < 0.01), 24h urinary sodium-to-potassium ratio (P-trend < 0.05), and fractional excretion of potassium (P-trend < 0.0001) were all higher as eGFR declined. In contrast, 24h urinary sodium excretion, plasma aldosterone and renin, did not differ across quartiles of eGFR. Conclusions: A continuum of higher plasma F/E, and biomarkers of MR activation, is observed with lower eGFR in individuals spanning a wide spectrum of kidney function, including those with apparently normal kidney function. These findings support the concept of progressive 11βHSD2 insufficiency as kidney function declines and implicate cortisol-mediated MR activation in the pathophysiology of hypertension and cardiovascular disease in CKD. Monday, June 3, 2024