Calcineurin inhibitor effects on kidney electrolyte handling and blood pressure: tacrolimus versus voclosporin

Abstract

ABSTRACT Background Calcineurin inhibitors (CNIs) affect kidney electrolyte handling and blood pressure (BP) through an effect on the distal tubule. The second-generation CNI voclosporin causes hypomagnesaemia and hypercalciuria less often than tacrolimus. This suggests different effects on the distal tubule, but this has not yet been investigated experimentally. Methods Rats were treated with voclosporin, tacrolimus or vehicle for 28 days. Dosing was based on a pilot experiment to achieve clinically therapeutic concentrations. Drug effects were assessed by electrolyte handling at day 18 and 28, thiazide testing at day 20, telemetric BP recordings and analysis of messenger RNA (mRNA) and protein levels of distal tubular transporters at day 28. Results Compared with vehicle, tacrolimus but not voclosporin significantly increased the fractional excretions of calcium (>4-fold), magnesium and chloride (both 1.5-fold) and caused hypomagnesaemia. Tacrolimus but not voclosporin significantly reduced distal tubular transporters at the mRNA and/or protein level, including the sodium–chloride cotransporter, transient receptor melastatin 6, transient receptor potential vanilloid 5, cyclin M2, sodium–calcium exchanger and calbindin-D28K. Tacrolimus but not voclosporin reduced the mRNA level and urinary excretion of epidermal growth factor. The saluretic response to hydrochlorothiazide at day 20 was similar in the voclosporin and vehicle groups, whereas it was lower in the tacrolimus group. The phosphorylated form of the sodium–chloride cotransporter was significantly higher at day 28 in rats treated with voclosporin than in those treated with tacrolimus. Tacrolimus transiently increased BP, whereas voclosporin caused a gradual but persistent increase in BP that was further characterized by high renin, normal aldosterone and low endothelin-1. Conclusions In contrast to tacrolimus, voclosporin does not cause hypercalciuria and hypomagnesaemia, but similarly causes hypertension. Our data reveal differences between the distal tubular effects of tacrolimus and voclosporin and provide a pathophysiological basis for the clinically observed differences between the two CNIs.