Drug-induced renal magnesium loss: a translational study with the focus on the mechanisms in the distal tubule
Datum: 12 december 2013
Locatie: UAntwerp - Campus Drie Eiken - Promotiezaal - Universiteitsplein 1 - 2610 Wilrijk
Tijdstip: 17 uur
Organisatie / co-organisatie: Faculty of Medicine and Health Sciences
Promovendus: Kristien Ledeganck
Promotor: Prof. De Winter
Korte beschrijving: PhD defence Kristien Ledeganck - Faculty of Medicine and Health Sciences
Abstract: Introduction: A lot of drugs are known to induce hypomagnesaemia due to renal magnesium loss among which cyclosporine and cisplatin. Since hypomagnesaemia may have serious clinical implications such as confusion, muscle weakness, tremor, dysphagia, tetany and general convulsions, it is important to gain knowledge about the mechanisms leading to hypomagnesaemia in order to treat the patients properly or to prevent these drug-induced side effects. In the kidney, the ionized serum magnesium is filtered by the glomerulus and the largest amount is reabsorbed along the tubules in a passive paracellular way. The fine-tuning occurs in the distal convoluted tubule, where magnesium is reabsorbed via the magnesium channel TRPM6. Recently, it was shown that EGF stimulates the magnesium reabsorption in the distal convoluted tubule via its receptor on the basolateral membrane and via activation of TRPM6 in the apical membrane.
Aim: In this thesis, we aimed to unravel the underlying mechanisms causing cyclosporine- and cisplatin-induced renal magnesium loss in vivo in rats as well as in patients.
Results: In both a cyclosporine and a cisplatin rat model we were able to show that a decreased renal magnesium reabsorption is associated with a downregulation of the renal EGF and TRPM6 mRNA expression levels while the expression levels of the more proximally located magnesium transport proteins, claudin-16 and claudin-19, were not decreased. In patients treated with cyclosporine, we found an association between a decreased renal EGF production and a decreased renal magnesium reabsorption, which is in accordance with the mechanisms unravelled in the cyclosporine rat experiment. From the interim analysis of the clinical study cisplatin-treated patients, we conclude that not all patients treated with cisplatin develop hypomagnesaemia. In the patients who do develop hypomagnesaemia, an increased renal magnesium loss was observed in conjunction with a decreased urinary EGF excretion. In both the clinical cisplatin and the clinical cyclosporine study, the urinary EGF concentration was related to the fractional excretion of magnesium, thereby confirming the role of EGF in the regulation of the magnesium reabsorption in humans.
Conclusion: EGF is a key player in the renal magnesium handling in vivo.