Endogenous urinary glucocorticoid metabolites and mortality in prednisolone-treated renal transplant recipients

Annet Vulto, Isidor Minović, Laura V de Vries, Arwin C Timmermans, Martijn van Faassen, Antonio W Gomes Neto, Daan J Touw, Margriet F C de Jong, André P van Beek, Robin P F Dullaart, Gerjan Navis, Ido P Kema, Stephan J L Bakker, Annet Vulto, Isidor Minović, Laura V de Vries, Arwin C Timmermans, Martijn van Faassen, Antonio W Gomes Neto, Daan J Touw, Margriet F C de Jong, André P van Beek, Robin P F Dullaart, Gerjan Navis, Ido P Kema, Stephan J L Bakker

Abstract

Background: Chronic corticosteroid treatment suppresses HPA-axis activity and might alter activity of 11β hydroxysteroid dehydrogenases (11β-HSD). We aimed to investigate whether the endogenous glucocorticoid production and 11β-HSD activities are altered in prednisolone-treated renal transplant recipients (RTR) compared with healthy controls and whether this has implications for long-term survival in RTR.

Methods: In a longitudinal cohort of 693 stable RTR and 275 healthy controls, 24-hour urinary cortisol, cortisone, tetrahydrocorisol (THF), allotetrahydrocortisol (alloTHF), and tetrahydrocortisone (THE) were measured using liquid chromatography tandem-mass spectrometry. Twenty-four-hour urinary excretion of cortisol and metabolites were used as measures of endogenous glucocorticoid production; (THF + alloTHF)/THE and cortisol/cortisone ratios were used as measures of 11β-HSD activity.

Results: Urinary cortisol and metabolite excretion were significantly lower in RTR compared with healthy controls (P < .001), whereas (THF + alloTHF)/THE and cortisol/cortisone ratios were significantly higher (P < .001 and P = .002). Lower total urinary metabolite excretion and higher urinary (THF + alloTHF)/THE ratios were associated with increased risk of mortality, independent of age, sex, estimated glomerular filtration rate, C-reactive protein, body surface area, and daily prednisolone dose, respectively.

Conclusions: Endogenous glucocorticoid production and 11β-HSD activities are altered in prednisolone-treated RTR. Decreased total urinary endogenous glucocorticoid metabolite excretion and increased urinary (THF + alloTHF)/THE ratios are associated with increased risk of mortality.

Trial registration: ClinicalTrials.gov NCT02811835.

Keywords: 11βHSD; cortisol; mortality; prednisolone; renal transplant recipients.

Conflict of interest statement

The authors declare no conflict of interest.

© 2020 The Authors. Clinical Transplantation published by John Wiley & Sons Ltd.

Figures

Figure 1
Figure 1
Supposed effects of prednisolone on cortisol production and metabolism. 11β‐HSD1, 11beta‐hydroxysteroid dehydrogenase type 1; 11β‐HSD2, 11beta‐hydroxysteroid dehydrogenase type 2; ACTH, adrenocorticotropic hormone; alloTHF, allotetrahydrocortisol; and PRED, prednisolone; CRH, corticotropin‐releasing hormone; THE, tetrahydrocortisone; THF, tetrahydrocortisol. Continuous lines represent known effects; dashed line represents hypothesized effects
Figure 2
Figure 2
Urinary [A] cortisol excretion, [B] cortisone excretion, [C] tetrahydrocortisol (THF) excretion, [D] allotetrahydrocortisol (alloTHF) excretion, [E] tetrahydrocortisone (THE) excretion, [F] total endogenous glucocorticoid (GC) metabolite excretion, [G] (THF + alloTHF)/THE ratio, and [H] cortisol/cortisone ratio in renal transplant recipients according to prednisolone dose compared with healthy controls, which are referred to as R (reference). *P < .05, ***P < .001
Figure 3
Figure 3
Association of total urinary endogenous glucocorticoid (GC) metabolite excretion with urinary (THF + alloTHF)/THE ratio in RTR and healthy controls. Controls: St. β = 0.03, 95%CI −0.09; 0.15, P = .65; RTR: St. β = −0.45, 95%CI −0.51; −0.40, P < .001

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