Hypermagnesuria in Humans Following Acute Intravenous Administration of Digoxin

Abstract

Background: Hypomagnesemia is a known predisposing condition for the appearance of digitalis toxicity. The detection of a genetic form of Mg urinary wasting with hypomagnesemia being caused by a mutation in the γ subunit (FXYD2) of the Na,K-ATPase, the pharmacological target of Digoxin, prompted us to investigate whether Digoxin administration increases urinary Mg excretion. Methods: Two groups of subjects, with rapid atrial fibrillation, received intravenous Digoxin (n = 9) or verapamil (n = 8), for heart rate control. During the following 4 h, blood and urinary creatinine, sodium, potassium, calcium, and magnesium levels were determined, and fractional excretion (Fex) values for Na, K, Ca, and Mg were calculated. Results: In the Digoxin group, at 60 min Fex Mg rose from 3.07 ± 1.21 to 7.58 ± 2.51% (an increase of 269 ± 107% of baseline, p < 0.001), and at 240 min to 6.05 ± 2.30% (204 ± 56% of baseline, p < 0.01). No significant change was observed for Fex Na, Fex K, and Fex Ca. A striking correlation was found between individual values of Fex Mg and serum Digoxin concentration (r = 0.678, p < 0.0001). No significant correlation was found between Fex Na or Fex K and serum Digoxin. A correlation of borderline significance was found between Fex Ca and serum Digoxin (r = 0.349, p = 0.073). Conclusions: The hypermagnesuric effect of acute Digoxin treatment is reminiscent of the effect of the missense mutation in FXYD2, which assumes that FXYD2 is a positive regulator of Na,K-ATPase in the distal convoluted tubule (DCT). The borderline calciuric effect of Digoxin may point to an additional site of action, more proximal to the DCT, that is, the thick ascending limb.

Renal Mg handling, FXYD2 and the central role of the Na,K-ATPase

“…In DCT this will compromise the ability to maintain the high intracellular K concentration that underlies the luminal membrane potential that drives Mg uptake. The end result will resemble the effect of acute Na,K-pump inhibition by digoxin (Abu-Amer et al 2018). In more proximal segments (PCT and TALH) the absence of ab-FXYD2 interactions should also lead to reduced Na,K-ATPase activity and lowered Mg reabsorption but, as with digoxin, this will not be fully compensated by increased Mg uptake in DCT.…”

“…The end result will resemble the effect of acute Na,K‐pump inhibition by digoxin (Abu‐Amer et al. ). In more proximal segments (PCT and TALH) the absence of αβ –FXYD2 interactions should also lead to reduced Na,K‐ATPase activity and lowered Mg reabsorption but, as with digoxin, this will not be fully compensated by increased Mg uptake in DCT.…”

“…Administration of digoxin to human patients to control rapid atrial fibrillation is associated with increased fractional excretion of Mg in the urine, Fex Mg, with borderline increased Fex Ca but unchanged Fex Na and K (Abu‐Amer et al. ). The effect is acute, occurring maximally after one hour and there is a striking correlation between Fex Mg and serum digoxin concentrations, which is in the range 0–5 nmol/L ( r = 0.68, P < 0.0001).…”

Digoxin and Hypermagnesuria

“…In an article published in this issue of Nephron, Abu-Amer et al [1] reported the presence of hypermagnesuria in patients following the acute intravenous administration of digoxin. The task of identifying drugs associated with increased magnesuria is clinically relevant, since hypermagnesuria can be associated with hypomagnesemia, which is a side effect of several drugs commonly used in the clinical practice and an emerging health problem with important clinical implications, including systemic (increased levels of C-reactive protein and tumour necrosis factor), renal (chronic kidney disease), neurologic (migraine, depression, epilepsy, neurodegenerative diseases), pulmonary (inflammation, bronchoconstriction), endocrine (metabolic syndrome, type II diabetes), cardiovascular (arrhythmias, coronary artery disease, arteriosclerosis, endothelial dysfunction), and bone complications (reduced osteoblast activity, low levels of parathyroid hormone, osteoporosis) [2].…”

“…The task of identifying drugs associated with increased magnesuria is clinically relevant, since hypermagnesuria can be associated with hypomagnesemia, which is a side effect of several drugs commonly used in the clinical practice and an emerging health problem with important clinical implications, including systemic (increased levels of C-reactive protein and tumour necrosis factor), renal (chronic kidney disease), neurologic (migraine, depression, epilepsy, neurodegenerative diseases), pulmonary (inflammation, bronchoconstriction), endocrine (metabolic syndrome, type II diabetes), cardiovascular (arrhythmias, coronary artery disease, arteriosclerosis, endothelial dysfunction), and bone complications (reduced osteoblast activity, low levels of parathyroid hormone, osteoporosis) [2]. In this regard, hypomagnesemia can be a consequence of reduced gastrointestinal absorption (i.e., after proton pump inhibitors administration [3]) or increased urinary excretion (i.e., after loop diuretics, calcineurin inhibitors or digoxin administration [1, 4, 5]; Fig. 1).…”