Tacrolimus‐induced hypomagnesemia and hypercalciuria requires FKBP12 suggesting a role for calcineurin

Abstract

Calcineurin inhibitors (CNIs) are immunosuppressive drugs used to prevent graft rejection after organ transplant. Common side effects include renal magnesium wasting and hypomagnesemia, which may contribute to new-onset diabetes mellitus, and hypercalciuria, which may contribute to post-transplant osteoporosis. Previous work suggested that CNIs reduce the abundance of key divalent cation transport proteins, expressed along the distal convoluted tubule, causing renal magnesium and calcium wasting. It has not been clear, however, whether these effects are specific for the distal convoluted tubule, and whether these represent off-target toxic drug effects, or result from inhibition of calcineurin. The CNI tacrolimus can inhibit calcineurin only when it binds with the immunophilin, FKBP12; we previously generated mice in which FKBP12 could be deleted along the nephron, to test whether calcineurin inhibition is involved, these mice are normal at baseline. Here, we confirmed that tacrolimus-treated control mice developed hypomagnesemia and urinary calcium wasting, with decreased protein and mRNA abundance of key magnesium and calcium transport proteins (NCX-1 and Calbindin-D 28k ). However, qPCR also showed decreased mRNA expression of NCX-1 and Calbindin-D 28k , and TRPM6. In contrast, KS-FKBP12 −/− mice treated with tacrolimus were completely protected from these effects. These results indicate that tacrolimus affects calcium and magnesium transport along the distal convoluted tubule and strongly suggests that inhibition of the phosphatase, calcineurin, is directly involved. K E Y W O R D Scalcineurin inhibitor, calcium, distal tubule, magnesium, tacrolimus CONFLICT OF INTERESTThere are no conflicts of interest to report.

Hypomagnesemia Is a Risk Factor for Infections after Kidney Transplantation: A Retrospective Cohort Analysis

“…However, the percentage of Mg 2+ deficiency was higher in patients with the highest tertile of serum tacrolimus concentrations. Adverse events of CNIs include renal Mg 2+ wasting leading to Mg 2+ deficiency [ 51 ]. Thus, CNIs might indirectly further increase the susceptibility of KTRs for viral infections.…”

Mechanisms coupling sodium and magnesium reabsorption in the distal convoluted tubule of the kidney

“…52,[81][82][83][84] Only drugs that affect both TRPM6 and NCC activity such as rapamycin and calcineurin inhibitors concomitantly result in Mg 2+ and Na + wasting. [85][86][87] Altogether, these findings suggest that Na + reabsorption affects Mg 2+ reabsorption in the DCT but not vice versa. From a physiological point of view, this would mean that the Mg 2+ reabsorption would be proportional to the Na + reabsorption in the DCT.…”

“…Drugs that reduce TRPM6 activity, eg EGFR inhibitors, cause hypomagnesaemia, but are not associated with increased Na + wasting 52,81‐84 . Only drugs that affect both TRPM6 and NCC activity such as rapamycin and calcineurin inhibitors concomitantly result in Mg 2+ and Na + wasting 85‐87 . Altogether, these findings suggest that Na + reabsorption affects Mg 2+ reabsorption in the DCT but not vice versa .…”

Genetic and drug-induced hypomagnesemia: different cause, same mechanism

“…Hypomagnesemia is almost always reported in cohorts of calcineurin inhibitor-treated patients, with incidences ranging from 10 to 50 % for CsA and from 50 up to 98 % for tacrolimus (97)(98)(99)(100)(101) . CsA and tacrolimus were found to reduce the expression of TRPM6 (102,103) . This effect may be mediated by the transcription factor c-Fos, as c-Fos is down-regulated by CsA and inhibition of c-Fos decreases both TRPM6 expression and Mg 2+ uptake (102) .…”