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

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 tandemmass 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. K E Y W O R D S 11βHSD, cortisol, mortality, prednisolone, renal transplant recipients S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section. How to cite this article: Vulto A, Minović I, de Vries LV, et al. Endogenous urinary glucocorticoid metabolites and mortality in prednisolone-treated renal transplant recipients. Clin

Glucocorticoid induced adrenal insufficiency

“…Inter-individual variability in the sensitivity of the HPAA to exogenous glucocorticoids has been observed 44128129. For example, higher cortisol after administration of dexamethasone was associated with an inadequate response to the low dose ACTH stimulation test after a 14 day course of prednisolone in healthy volunteers 44.…”

Sex- and age-specific reference intervals for diagnostic ratios reflecting relative activity of steroidogenic enzymes and pathways in adults

“…Age- and sex-related values provided for ratio 47 and ratio 49, both reflecting 5α-reductase deficiency, published by C. W. Weykamp et al in 1989 were all within current reference intervals [ 14 ]. The same applied for values obtained from different publications: (1) by Farese et al in 1991 concerning ratios 49, 56 and 57, the latter two reflecting 11β-HSD type 1 deficiency, (2) by Soro et al in 1995 concerning ratio 49 and ratio 53 (11β-HSD type 1 deficiency), (3) by Finken et al in 1999 concerning ratio 49 and ratio 52 (11β-HSD type 1 deficiency), and (4) by Vulto et al in 2020 concerning ratio 52 and ratio 53 [ 15 – 17 , 20 ]. Values published by Finken et al in 1999 for ratio 53 were remarkably higher than the current reference intervals for both sexes and also higher than all other corresponding values cited in S1 Table .…”

“…Ratios Ratio ID References 11βOHET/11βOHAT [9][10][11][12] THF/5αTHF [9][10][11][12][13][14][15][16][17][18] THB/5αTHB [9][10][11][12][13] CYP19A1/Aromatase deficiency (CYP19A1D) testosterone/17β-estradiol [9] 11β-hydroxysteroid dehydrogenase type 2 deficiency (11βHSD2D) c F/E [9,11,12,15,19,20] (THF+5αTHF)/THE [9][10][11][12][13]15,[17][18][19][20][21] (αC+βC)/(αCl+βCl) [9] (F+E)/(THF+5αTHF+THE) [9] 11β-hydroxysteroid dehydrogenase type 1 deficiency (11βHSD1D) d THE/(THF+5αTHF) [9][10][11][12]14,16] (αCl+βCl)/(αC+βC) [9,11,12,16] 20α-hydroxysteroid dehydrogenase (20αHSD) (THF...…”

Rationale and design of the CORE (COrticosteroids REvised) study: protocol

“…This study is designed as a cross-over trial as previous studies have demonstrated a high interindividual variation for the effect of exogenous corticosteroids 16 17. One intervention consists of two doses of prednisolone (11β,17,21-trihydroxy-1,4-pregnadieen-3,20-dion).…”