Renal Adaptation to Gentamicin-Induced Mineral Loss

Abstract

Background: Gentamicin, a well-known nephrotoxic drug, affects calcium and magnesium homeostasis. Although gentamicin induces urinary calcium and magnesium wasting immediately, it rarely causes significant hypocalcemia or hypomagnesemia clinically. Methods: We conducted an animal study to investigate the renal adaptation in calcium and magnesium handling after gentamicin treatment and effects on the expression of calcium and magnesium transport molecules in distal tubule. Gentamicin (40 mg/kg) was injected daily in male Sprague-Dawley rats (220–250 g) for up to 7 days. Results: This treatment did not affect serum creatinine, calcium, or magnesium levels. Gentamicin induced significant hypercalciuria (14-fold) and hypermagnesiuria (10-fold) in 6 h, which was associated with upregulation of TRPV5 (175 ± 3%), TRPV6 (170 ± 4%), TRPM6 (156 ± 4%) and calbindin-D28k (174 ± 3%; all p < 0.05 vs. control). This gene upregulation was maintained with daily injection of gentamicin for 7 days. The gentamicin-induced urinary calcium loss was reduced by 80% at days 3 and 7, while magnesium loss was reduced by 52 and 57% at days 3 and 7, respectively. On the other hand, urinary loss of potassium became worse on day 7 (2-fold), and phosphorus loss worse from day 3 to day 7 (3-fold). Conclusion: There is a rapid adaptation to gentamicin-induced hypercalciuria and hypermagnesiuria. The upregulation of distal tubule transport molecules, TRPV5, TRPV6, TRPM6 and calbindin-D28k occurs within 6 h of gentamicin treatment. This renal adaptation prevents further mineral loss due to gentamicin treatment.

The role of calbindin-D28k on renal calcium and magnesium handling during treatment with loop and thiazide diuretics

“…To compensate for the large loss of Ca, active Ca transporters such as TRPV5 and TRPV6 in the downstream DCT are upregulated (15). A similar compensatory mechanism has been reported in the gentamicin-and diabetes-induced hypercalciuria by our group (14,16). Thiazides induce hypocalciuria via different mechanisms depending on the volume status: with volume depletion, increased passive reabsorption in PT is the key mechanism (18); without volume depletion, the increased Ca reabsorption mainly occurs in the DCT via upregulation of TRPV5/6 and CBD-28k (13).…”

“…A genetic defect in claudin-16 causes hypomagnesemia with hypercalciuria and nephrocalcinosis (9). The expression of claudin-16 is not affected by salt or fluid intake (17), or Mg-wasting drugs such as gentamicin (16) and cisplatin (11). Since CTZ acts on the DCT, it is unlikely to affect the expression of claudin-16, which locates to the TALH.…”

Effect of intravenous gentamicin on urinary calcium excretion in newborns

“…1,2 Some studies in newborns and animals have shown that gentamicin increases urinary calcium excretion. [11][12][13][14][15] Injection every 36-48 hours is a new recommendation for intravenous gentamicin treatment in newborns. 3 Following this new recommendation, there have been no further studies on the effects of extended gentamicin dosage on urinary calcium excretion in newborns.…”

Magnesium homeostasis and hypomagnesemia in children with malignancy

“…Among the other group of medications often used in children with malignancy, it is believed that calcineurin inhibitors, cyclosporine and tacrolimus, often used in transplanted patients are causing hypomagnesemia by decreasing both sodium reabsorption and TRPM-6 expression in the distal tubule thus causing renal magnesium wasting [23,24,61]. As depicted in Figure 2, gentamicin and other aminoglycosides exert their magnesuric effect by stimulating the calcium sensor receptor located at the basolateral side of the thick ascending limb of the loop of Henle [35,62]. Physiologically the activation of the receptor by hypercalcemia and hypermagnesemia causes decreased sodium reabsorption and consequently that of magnesium.…”