The effect of spironolactone upon corticosteroid hormone metabolism in patients with early stage chronic kidney disease.
BACKGROUND
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 in these patients, little is known about the effects on corticosteroid hormone secretion and metabolism.


OBJECTIVE
To assess corticosteroid hormone secretion and metabolism in patients with early stage CKD before and after spironolactone (Spiro).


METHODS
Randomized, double-blind, placebo-controlled interventional study.


METHODS
Single tertiary referral centre.


METHODS
A total of 112 patients with stable stage 2/3 CKD.


METHODS
Patients were randomized to receive either Spiro 25 mg once daily or placebo for 36 weeks.


METHODS
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.


RESULTS
Plasma aldosterone concentration (PAC) was inversely correlated with eGFR (r = -0·331, P < 0·001). Urinary 24-h excretion of TH-Aldo was correlated with PAC (r = 0·214, P < 0·05) and diastolic blood pressure (BP) (r = 0·212, P = <0·05), whereas total 24-h 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 renin-angiotensin-aldosterone system induction, reflected by increased urinary 24-h TH-Aldo excretion (17·6 (12, 86) vs 26 (18, 80) μg/24 h, 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 24-h corticosteroid production.
Hammer
Fabian
F
School of Clinical and Experimental Medicine, University of Birmingham, University Hospitals Birmingham Foundation NHS Trust, Edgbaston, Birmingham, UK. p.m.stewart@bham.ac.uk
Edwards
Nicola C
NC
Hughes
Beverly A
BA
Steeds
Richard P
RP
Ferro
Charles J
CJ
Townend
Jonathan N
JN
Stewart
Paul M
PM
D000305:Adrenal Cortex Hormones / Q000378:metabolism* / Q000652:urine; D000328:Adult; D000368:Aged; D000450:Aldosterone / Q000378:metabolism; D000804:Angiotensin II / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D007676:Kidney Failure, Chronic / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D000451:Mineralocorticoid Receptor Antagonists; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy / Q000378:metabolism*; D012083:Renin / Q000097:blood; D013148:Spironolactone / Q000627:therapeutic use*; D013760:Tetrahydrocortisol / Q000652:urine
D000305:Adrenal Cortex Hormones; D000451:Mineralocorticoid Receptor Antagonists; D000804:Angiotensin II; D013148:Spironolactone; D000450:Aldosterone; D013760:Tetrahydrocortisol; D012083:Renin; D006854:Hydrocortisone