IES2025 Oral Communications Oral Communications (14 abstracts)
Steroid metabolome profiling reveals impaired 11β-hydroxysteroid dehydrogenase type 2 activity and reduced mineralocorticoid clearance as key predictors of renal dysfunction in chronic kidney disease
Maria Tomkins 1,2 , Darran McDonald 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 , 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
Increased activation of the mineralocorticoid receptor (MR) contributes to progressive kidney and cardiovascular injury in chronic kidney disease (CKD). The enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) plays a critical protective role by converting active cortisol (F) to inactive cortisone (E), preventing glucocorticoid-mediated MR activation. In this study, we sought further understanding of endogenous steroid regulation by studying mineralocorticoid and glucocorticoid metabolism in CKD. Using paired serum and 24-hour urine samples, we conducted targeted steroid profiling via liquid chromatography–tandem mass spectrometry in patients with CKD (n = 103) and matched healthy controls (n = 50). Despite elevated plasma aldosterone concentrations (357 pmol/l in CKD vs; 235 pmol/l in controls, P = 0.01), patients with CKD had significantly lower total urinary mineralocorticoid metabolites (398 nmol/l in CKD vs; 882 nmol/l in controls, P < 0.0001), suggesting impaired renal clearance. 11β-HSD2 activity declined with worsening renal function evidenced by an elevated F/E ratio (11.1 in CKD vs 5.7 in controls, P < 0.0001). There was a strong inverse correlation between eGFR and F/E (Spearman r = –0.75, P < 0.0001). Multivariable regression identified elevated serum aldosterone, lower total urinary mineralocorticoid metabolites and increased F/E ratio as independent predictors of lower eGFR when accounting for age, sex, antihypertensives, urine volume and urine creatinine concentration.The reduced 11β-HSD2 activity and renal clearance of mineralocorticoids demonstrated potentiates MR activity in CKD. This is the first study to interrogate the complete urine steroid metabolome in CKD providing an insight into renal determinants of steroid metabolism. It also highlights potential diagnostic implications for the use of urine steroid metabolomics in CKD.
Volume 115
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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