IES2025 Oral Communications Oral Communications (14 abstracts)
Impaired glucocorticoid metabolism independently predicts cardiovascular morbidity in chronic kidney disease
Maria Tomkins 1,2 , Darran Mc Donald 1,2 , Fozia Shaheen 3 , Angela E Taylor 3 , Declan de Freitas 2 , Carol Traynor 2 , Amy Hudson 2 , Ciara N. Magee 2 , Peter Conlon 2 , Colm Magee 2 , Mark Denton 2 , Conall O’Seaghdha 2 , Diarmuid Smith 2, , Wiebke Arlt 3,4,5 , Michael W. O’Reilly 1,2 & Mark Sherlock 1,2
1Royal College of Surgeons in Ireland, Dublin; 2Beaumont Hospital, Dublin; 3Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK; 4Medical Research Council Laboratory of Medical Sciences, London, UK; 5Institute of Clinical Sciences, Imperial College London, London, UK
Patients with chronic kidney disease (CKD) have an elevated risk of cardiovascular disease (CVD) potentiated by mineralocorticoid receptor (MR) overactivation. MR activation occurs from both mineralocorticoid and inappropriate glucocorticoid binding. The enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) converts active cortisol (F) to inactive cortisone (E) thereby protecting the MR, and its activity has been shown to be impaired in CKD. To investigate the contribution of disrupted adrenal steroid metabolism to CVD risk in CKD we performed liquid chromatography–tandem mass spectrometry on paired serum and 24-hour urine samples from non-diabetic CKD patients (n = 103) and age-, sex-, and BMI-matched healthy controls (n = 39) alongside detailed cardiometabolic phenotyping, including pulse wave velocity (PWV) and body composition analysis. CKD patients had higher HOMA-IR (2.6 VS 2.0, P = 0.01), and PWV (5.9 vs 5.3m/s, P = 0.0007), with comparable BMI, body composition, and blood pressure compared to controls. CKD patients had elevated ACTH (25.3 vs 19.6pg/ml, P = 0.02), F/E ratio (11.1 vs 5.7 P < 0.0001), renin (58.0 vs 27.1mIU/l, P = 0.0005), and aldosterone (357 vs; 235 pmol/l, P = 0.01), alongside reduced urinary excretion of total glucocorticoid (6847 vs; 8094 nmol/l, P = 0.0002) and mineralocorticoid (398 vs; 882 nmol/l, P < 0.0001) metabolites compared to controls. Multiple regression revealed an independent association of both the F/E ratio (β=0.1, P = 0.04) and total urinary glucocorticoid metabolites (β=0.09, P = 0.007) with increased PWV, controlling for age, sex, renal function, blood pressure, and antihypertensive use. Mineralocorticoid markers showed no independent associations with cardiometabolic outcomes. Our findings highlight the important role of impaired 11β-HSD2 activity, reflected by an elevated F/E ratio, in driving glucocorticoid-mediated MR activation and arterial stiffness.
Volume 115
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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