Pascalle van den Wijngaard1, Annet Vulto1, Suzanne Stam2, Daan Kremer2, J Tomlinson3, Martin de Borst2, Michiel Kerstens1, Michel Vos4, Stephan Bakker2, André van Beek1
(1) UMCG, Department of Internal Medicine, Division of Endocrinology, Groningen, The Netherlands. (2) UMCG, Department of Internal Medicine, Division of Nephrology, Groningen, The Netherlands. (3) Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom. (4) UMCG, Department of Laboratory Medicine, Groningen, The Netherlands.
Background:
Long-term graft survival remains a paramount challenge in kidney transplant recipients (KTR). One emerging therapeutic avenue of exploration involves the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) with its pivotal role in intracellular amplification of glucocorticoid levels. Its activity has been implicated in various metabolic complications, however its role on kidney graft survival is not yet known.
Methods:
In a prospective cohort study of 662 KTR and 103 healthy controls, 24-hour urinary tetrahydrocortisol (THF), allotetrahydrocortisol (alloTHF), and tetrahydrocortisone(THE) were measured using liquid chromatography tandem-mass spectrometry. (THF + alloTHF)/THE was used as measurement of 11β-HSD1 activity. All included KTR were treated with prednisolone.
Results:
Activity of 11ß-HSD1 was higher in KTR 1.7 [1.4-2.2] compared to controls (1.2 [0.94-1.4], P<0.001). During a median follow-up of 5.3 [4.5-6.0] years 12% KTR developed graft failure. In Cox regression survival analyses 11ß-HSD1 activity was associated with graft failure (HR 1.93 95% [1.44-2.58]; P <0.001 per unit increase of log2-transformed 11ß-HSD1 activity), independent of sex, age, lipoproteins, glucose, donor status, and use of calcineurin inhibitors and only lost its significance after adjustment for renal function.
Conclusion:
Increased 11ß-HSD1 activity is strongly associated with a higher risk of graft failure in KTR. Pharmacotherapeutic inhibition of 11ß-HSD1 activity may be a potential strategy to reduce graft failure.