Hypomagnesemia in the Cancer Patient

Abstract

Hypomagnesemia is a common medical problem that contributes to the morbidity and mortality of patients with cancer. This review summarizes magnesium physiology and highlights the mechanisms underlying magnesium disturbances due to cancer and cancer treatment. The causes of hypomagnesemia can be categorized according to the pathophysiologic mechanism: decreased intake, transcellular shift, gastrointestinal losses, and kidney losses. Patients with cancer are at risk for opportunistic infections, frequently experience cardiovascular complications, and often receive classes of medications that cause or exacerbate hypomagnesemia. Also, cancer-specific therapies are responsible for hypomagnesemia, including platinum-based chemotherapy, anti-EGF receptor mAbs, human EGF receptor-2 target inhibitors (HER2), and calcineurin inhibitors. Urinary indices, such as the fractional excretion of magnesium, can provide useful information about the etiology. The management of hypomagnesemia depends on the magnitude of hypomagnesemia and the underlying cause. We recommended checking serum magnesium at the beginning of treatment and as part of routine monitoring throughout cancer treatment. Opportunities exist for potential research and practice improvement, including further characterization of hypomagnesemia regarding the clinical effect on cancer outcomes, preventing hypomagnesemia in patients receiving high-risk anticancer agents, and developing effective therapeutic strategies.

Keywords: TRPM6; acid/base and electrolyte disorders; cetuximab; cisplatin; electrolytes; hypomagnesemia; magnesium; neoplasms; onconephrology.

Figure 1.

Kidney handling of magnesium (Mg) and nephron site of action of magnesiuric drugs. Numbers in blue (%) refers to the percent Mg that is reabsorbed in the specific segment of the nephron. Nonprotein-bound Mg is freely filtered across the glomerulus. The proximal tubule (PT) reabsorbs 15% of filtered magnesium via a paracellular mechanism. The bulk of Mg reabsorption occurs in the cortical thick ascending limb of the loop of Henle (TAL), where approximately 70% of Mg is reabsorbed via a paracellular route. Claudins 16 and 19 are considered the main claudins responsible for the Mg permeability through the paracellular route. Claudin 14 may interact with claudin 16 in TAL and decreases the cation selectivity of the claudin-16 and -19 complexes. Recently, claudin 10 has also been identified as an important factor in cation selectivity in TAL. The driving force for paracellular Mg reabsorption is the lumen-positive transepithelial voltage of the TAL, which is determined by the activity of NKCC2 and the subsequent potassium recycling back into the lumen via the ROMK channel at the apical membrane. Cl ions leave the TAL cells via ClC-Kb channels on the basolateral membrane. Activation of the CaSR in the TAL inhibits paracellular Mg transport via inhibition of NKCC2 and ROMK. Further, CaSR regulates claudin-14 expression and calcium and Mg reabsorption in the TAL. Aminoglycosides target the CaSR and foscarnet can chelate the Mg molecule. The site for fine-tuning magnesium regulation is the distal convoluted tubule (DCT), which is responsible for the reabsorption of 10% of filtered magnesium. No Mg reabsorption takes place beyond the DCT. Mg is reabsorbed in this nephron segment via the transcellular route through the TRPM6 Mg channels. EGF regulates TRPM6 by increasing its expression. EGF is synthesized as pro-EGF, which is then secreted by DCT cells to undergo cleavage by extracellular proteases to become EGF. EGF then binds to the EGFR at the basolateral membrane, thereby activating a tyrosine kinase, which stimulates TRPM6. NCC seems to be involved in Mg reabsorption in the DCT. Mg transport via TRPM6 depends almost exclusively on the negative membrane potential in the DCT cells because no significant chemical gradient for Mg exists in this nephron segment. Kiv1.1 is primarily responsible for maintaining the necessary negative membrane potential for Mg reabsorption in the DCT by providing an efflux of potassium, resulting in hyperpolarization of the luminal membrane. The activity of the Na-K-ATPase in the basolateral membrane also affects the membrane potential and is the driving force for Mg reabsorption. The FXYD2 gene encodes for the γ-subunit of the Na-K-ATPase. The transcription factor hepatocyte NF 1β (HNF1B) regulates the expression of FXYD2. The PCBD1 gene encodes for pterin-4a carbinolamine dehydratase, which is a dimerization cofactor for HNF1B. The activity of the Na-K-ATPase is also dependent on potassium recycling via Kir4.1 channels in the basolateral membrane. The elucidation of the mechanism for basolateral Mg extrusion in the DCT has been challenging because there is no chemical gradient for Mg and the electrical gradient favors Mg uptake rather than extrusion. Therefore, it is likely that Mg extrusion is dependent on the sodium gradient set by the Na-K-ATPase. Several proteins in the basolateral membrane of DCT cells have been postulated to mediate Mg transport into the bloodstream. SCL41A3 and CNNM2 have been identified as potential Mg transporters in the basolateral membrane of DCT cells. Calcineurin and mTOR inhibitors affect the TRPM6 channel, and EGFR monoclonal antibodies and HER-2 inhibitors inhibit the basolateral EGFR. Cisplatin and pentamidine affect the transport of the Mg within the DCT (not shown in the figure). Ca²⁺, calcium ion; CaSR, calcium-sensing receptor; Cl⁻, chloride ion; ClC-Kb, Cl channel Kb; CNNM2, cyclin and CBS domain divalent metal cation transport mediator 2; EGFR, EGF receptor; FXYD2, FXYD domain containing ion transport regulator 2; K⁺, potassium ion; Kir4.1, inwardly rectifying potassium channel subtype 4.1; Kv1.1, voltage-gated potassium channel; Mg²⁺, Mg ion; mTOR, mammalian target of rapamycin; Na⁺, sodium ion; NCC, Na⁺-Cl⁻ cotransporter; NKCC2, Na⁺-K⁺-2Cl⁻ cotransporter; PCBD1, pterin-4a carbinolamine dehydratase; ROMK, renal outer medullary K⁺ channel; SLC41A3, solute carrier family 41 member 3; TRPM6, transient receptor potential cation channel subfamily M member 6.