The effect of Spironolactone upon corticosteroid hormone metabolism in patients with early stage chronic kidney disease

Fabian Hammer (1) , Nicola C Edwards (2) , Beverly A Hughes (1) , Rick Steeds (2) , Charles J Ferro (3) , Jonathan N Townend (2) , Paul M Stewart (1)

1 School of Clinical and Experimental Medicine
2 Department of Cardiology
3 Department of Nephrology

Context Aldosterone has emerged as an important mediator of disease progression and mortality in patients with chronic heart and kidney disease (CKD). Despite the increasing use of mineralocorticoid receptor antagonists (MRAs) in these patients little is known about the effects on corticosteroid hormone secretion and metabolism. Objective To assess corticosteroid hormone secretion and metabolism in early stage CKD patients before and after spironolactone (Spiro). Design Randomised, double-blind, placebo-controlled interventional study. Setting Single tertiary referral center. Patients 112 patients with stable stage 2/3 CKD. Interventions Patients were randomised to receive either Spiro 25mg once daily or placebo for 36 weeks. Main Outcome measures Plasma renin activity (PRA), angiotensin II (AngII) and steroid hormones were analysed by standard assays, urinary corticosteroid hormone metabolites (5α+5β-tetrahydro cortisol (5α+5β-THF), TH–cortisone (THE), 3α5β-TH-aldosterone (TH-Aldo), 5α+5β-TH-deoxycorticosterone (5α+5β-TH-DOC), TH-11-desoxycortisol (THS)), were analysed by gas chromatography/mass spectrometry (GC/MS). Results Plasma aldosterone concentration was inversely correlated with eGFR (r= -0.331, p<0.001). Urinary 24h excretion of TH-Aldo was correlated with plasma Aldo concentration (PAC) (r=0.214, p<0.05) and diastolic blood pressure (BP) (r=0.212, p=<0.05), whereas total 24h urinary cortisol metabolite excretion was correlated with systolic BP (r=0.316, p<0.01). In addition, 11β-hydroxysteroid dehydrogenase (11β-HSD) type 1 activity (urinary 5α+5β-THF) / THE) ratio) was correlated with PRA (r=0.277,p<0.01). Spiro treatment significantly reduced BP (123±11/76±7 vs 119±11/73±8 mmHg, p<0.01) despite RAAS induction, reflected by increased urinary 24h TH-Aldo excretion (17.6 (12,86) vs 26 (18,80) μg/24h, p<0.05). By contrast, Spiro had no effect on total urinary cortisol metabolite excretion, 11β-hydroxylase, 11β-HSD type 1 and 2 activity. Conclusions Aldo and cortisol are positively associated with BP suggesting that adrenal hyperactivity may in part explain the increased cardiovascular risk in patients with early end-stage CKD. Addition of Spiro had no effect on glucocorticoid metabolism or total 24h corticosteroid production.

Mots clés: Medicine

Fabian Hammer, Nicola C Edwards, Beverly A Hughes, Rick Steeds, Charles J Ferro, et al.. The effect of Spironolactone upon corticosteroid hormone metabolism in patients with early stage chronic kidney disease. Clinical Endocrinology, 2010, 73 (5), pp.566. ⟨10.1111/j.1365-2265.2010.03832.x⟩. ⟨hal-00552610⟩