Electrolyte disorders with platinum-based chemotherapy: mechanisms, manifestations and management

The fourth most abundant cation, and crucial cofactor in >300 enzymatic reactions including the sodium–potassium pump or Na–K ATPase [4], magnesium is predominantly located intracellularly or deposited in bone; thus, serum levels are poor indicators of total body stores and the presence of hypomagnesemia defined as a concentration <1.5 mEq/L usually indicates a more severe underlying cellular deficit [4]. Conversely, tissue deficiency may be present despite normal serum levels.

Therefore, hypomagnesemia and magnesium deficiency are not interchangeable or synonymous terms even though they are commonly used as such. Plasma concentrations are reported in mEq/L versus units or grams for replacement therapy. Only 55% of the total serum concentration circulates in the ionized or physiologically active form, with the rest bound to albumin or chelated to anions (e.g., phosphate, oxalate, citrate or sulfate [5]), and unlike techniques for measuring ionized calcium, ionized magnesium testing is not routinely available [6]. Because approximately 30% of magnesium is bound to albumin, hypoalbuminemic states may lead to low magnesium values [7].

Total serum magnesium is present in three different states (Fig. 1). Because of different measurement methods, results published for each state of serum magnesium vary considerably. Therefore, a range for every state is provided.

Magnesium deficiency is fairly widespread even in the absence of platinum therapy [8]; however, it is usually not recognized and therefore not found or corrected. Gastrointestinal and renal losses are the two major mechanisms responsible for the induction of magnesium deficiency and hypomagnesemia [9]. Because the mobilization of magnesium from the skeleton is exceedingly slow [10], magnesium deficiency not only occurs relatively quickly with minimal losses but also takes longer to normalize.

The concentration of magnesium (Mg⁺⁺) significantly influences serum levels of other electrolytes such as potassium, calcium and phosphate [11], which points out the centrality of its position and role. In terms of this review, a low magnesium state is particularly associated with cisplatin (and to a much lesser extent carboplatin [12]) therapy, more so than any other electrolyte deficiency, affecting 40–90% of patients [13] as opposed to 10% of patients treated with carboplatin [14].

Platinum-induced hypomagnesemia, which has been reported to persist for up to 6 years after cessation of treatment [15], is primarily attributed to renal magnesium wasting and/or reduced intestinal absorption. Additional factors discussed below that can exacerbate magnesium deficiency include drugs, endocrine causes and alcoholism (Table 1).

Loop diuretics (e.g., furosemide) cause magnesium depletion via inhibition of magnesium transport in the ascending loop of Henle, especially during long-term use [20], while thiazide diuretics (e.g., HCTZ) lead to urinary magnesium losses [21] through increased solute diuresis. By the same mechanism, polyuric states due to diabetes mellitus (osmotic diuresis), post-obstructive diuresis, mannitol administration, hyperaldosteronism and volume expansion from normal saline, a common cause of hypomagnesemia in hospitalized patients, may induce magnesium deficiency. If possible, loop or thiazide diuretics should be discontinued during platinum therapy and replaced with potassium-sparing diuretics such as spironolactone, triamterene or amiloride [22], which also exert magnesium-sparing properties.

These antibiotics including gentamicin, tobramycin and amikacin, which accumulate in and preferentially damage proximal tubular cells, are known to cause hypomagnesemia, and the use of alternative agents should be considered, if possible, during platinum therapy [23].

Hypomagnesemia may occur with bisphosphonates as a result of binding of the bisphosphonates to magnesium cations [24].

Patients with lung cancer and COPD under long term or acute therapy with inhaled or systemic corticosteroids and β₂-agonists are also at risk for hypomagnesemia. Corticosteroids (e.g., dexamethasone) may also be given as a premedication to prevent cisplatin-induced nausea and vomiting. Close monitoring and regular supplementation with magnesium should be considered in these cases: beta-adrenergic stimulation not only induces an extracellular to intracellular shift of magnesium ions but also results in higher levels of free fatty acids that chelate Mg⁺²; [25, 26] corticosteroid use, which also leads to bone loss from renal excretion and suppressed intestinal absorption of calcium, may secondarily cause a net negative magnesium balance due to increased bone resorption and renal wasting.

Insulin modulates the shift of magnesium from extracellular to intracellular space, which may exacerbate low Mg⁺⁺ levels [27]. In addition, poorly controlled diabetes may result in renal magnesium wasting secondary to the osmotic diuresis from hyperglycosuria. Evaluation of magnesium status in diabetic patients, especially poorly controlled and/or insulin-dependent diabetic patients, is recommended.

Cetuximab (Erbitux) and panitumumab (Vectibix), monoclonal antibodies, which bind specifically to EGFR, are associated with a high rate of hypomagnesemia (60% in the case of cetuximab). The mechanism is related to inhibition of the Mg²⁺ channel TRPM6 (Transient Receptor Potential Melastatin subtype 6/7), which regulates magnesium absorption in the gut and renal tubules [28]. Suspicion of Mg²⁺ deficiency should be particularly elevated in patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC [29]) where cetuximab in combination with platinum and 5FU is administered as the first-line standard of care.

As discussed above, magnesium absorption occurs in the gut primarily through the Mg2 + influx channel, Transient Receptor Potential Melastatin 6 (TRPM6/7) [30], also found in the distal renal tubule, which is pH sensitive. PPI use, which leads to alkalization of the intestinal lumen, changes the TRPM6/7 channel affinity for Mg²⁺ and inhibits magnesium absorption [31]. In this way, PPIs such as lansoprazole, omeprazole, rabeprazole and esomeprazole may induce hypomagnesemia refractory to oral supplementation [32].

Early signs of magnesium deficiency including loss of appetite, nausea, vomiting, fatigue and weakness [35] are confounding because these same adverse events commonly occur with platinum therapy. As magnesium deficiency worsens a depolarization shift of the membrane occurs, potentially resulting in behavioral changes (e.g., confusion, agitation, depression), neuromuscular excitability (e.g., numbness, tingling, hyperactive deep tendon reflexes, muscle contractions, cramps and seizures) and cardiac effects including arrhythmias [36] (ventricular tachycardia, Torsade de pointes, ventricular fibrillation), abnormal electrical activity (prolonged QT and QU interval), potentiation of digitalis effects and vascular tone [37]. With severe hypomagnesemia, low levels of calcium and potassium in the blood may be observed and, on physical exam, similar to manifestations of hypocalcemia, the Chvostek (twitching of facial muscles in response to tapping over the facial nerve in front of the ear) and Trousseau (spasm of the hands induced by an inflated blood pressure cuff on the arm) signs of latent tetany may be elicited [38].

However, it is important to note that even in severely hypomagnesemic patients, clinical signs or red flags may be few, non-obvious or absent [39]. In addition, the presence of symptoms is more common in patients that experience a rapid rather than a gradual decrease in serum magnesium. Due to the lack of accurate diagnostic studies, a presumptive diagnosis of low magnesium is often warranted whether or not symptoms are present since, if left untreated, the potential exists for catastrophic outcomes (e.g., death from cardiac arrhythmias).

Traditionally, the management of hypomagnesemia has been based on the NCI grading criteria shown below [40]:

However, since measurement of serum levels may not be accurate or diagnostic, the decision to treat should be based on the strength of belief and clinical judgment (in other words, pretest probability) taking into account comorbidities such as diabetes or heart disease, which make dangerous arrhythmias more likely, concomitant medications that predispose to magnesium losses such as diuretics, bisphosphonates, proton pump inhibitors, beta-2 agonists and corticosteroids, and miscellaneous factors including alcohol intake, blood transfusions and calcium levels. Electrolyte abnormalities that converge on hypomagnesemia and serve as important diagnostic clues to its presence include concomitant hypokalemia (due to impaired Na–K–ATPase and urinary potassium wasting) and hypocalcemia (due both to lower parathyroid hormone secretion and end-organ resistance to its effect [41]); therefore, measurement of potassium and calcium levels should be sought as supportive evidence.

The two preferred agents for repletion are i.v. magnesium sulfate (2–4 g) and oral magnesium oxide [42]. Additional oral preparations include magnesium gluconate and magnesium sulfate along with sustained-release preparations such as Slow-Mag and Mag-Tab SR. The usual therapeutic dose of oral magnesium oxide is 400–800 mg per day with the caveat that at doses >400 mg diarrhea is likely to result, which increases magnesium excretion. Similar to glucocorticoid supplementation therapy during surgery or medical illness, patients may require additional magnesium doses during acute ill health, especially when vomiting and diarrhea are present.

Because excess magnesium is efficiently eliminated in the urine and plasma levels are closely maintained between 1.5 and 2.1 mEq/L, hypermagnesemia (>2.6 mg/dL) is a rare complication except in the setting of renal insufficiency (high creatinine or low glomerular filtration rate), which is the most common acute toxicity of platinum agents. Initial symptoms of hypermagnesemia, such as nausea, vomiting, lethargy and weakness are nonspecific but may rapidly progress to respiratory depression, prolonged PR and QT intervals on an ECG, hypotension, ventricular arrhythmias, cardiac arrest and death [43]. When renal function is impaired, treatment includes discontinuation of magnesium administration, increased fluid intake and loop diuretics. Calcium gluconate, a magnesium antagonist, is generally reserved for life-threatening symptoms, such as arrhythmia or severe respiratory depression.

In addition to low magnesium, platinum agents may also cause other electrolyte abnormalities including hypokalemia, hypocalcemia, hypophosphatemia and hyponatremia, discussed below. Hypokalemia, hypocalcemia and hypophosphatemia are considered together because of their relationship to magnesium deficiency and refractoriness to correction prior to magnesium repletion. However, even in the absence of low magnesium, renal potassium, calcium and phosphate wasting may occur as a result of platinum-mediated damage to tubular membranes.

Mild hypokalemia >2.5 mmol/L is often symptomatic [50]. Below 2.5 mmol/L, the leading symptoms of hypokalemia are muscle weakness, muscle pain, ileus and cramps [51]. With severe hypokalemia, rhabdomyolysis or paralysis may occur.

Mild hypocalcemia is usually asymptomatic, but perioral numbness and carpopedal spasms of the hands and feet, which in some cases may progress to tetany, are typical of large or abrupt changes in ionized calcium [58]. Chvostek’s sign (facial twitch from tapping on the facial nerve near the temporal mandibular joint) and Trousseau’s sign (hand flexion after inflating a blood pressure cuff on the arm for 3 min) are both clinical tests for this increased neuromuscular reactivity. Hypocalcemia may also progress to heart block and ventricular fibrillation.

The workup for hypocalcemia should include measurement of ionized calcium, serum magnesium, intact PTH (iPTH) and vitamin D (Fig. 4).

The correction of magnesium and phosphate should precede the correction of calcium. 1–2 g of elemental calcium per day may be sufficient for mild hypocalcemia. Intravenous calcium infusions are only indicated in the setting of symptomatic or severe (<7.0 mg/dL or <0.8 mmol/L) hypocalcemia. The preferred form is calcium gluconate. If appropriate, thiazide diuretics, which diminish the renal excretion of calcium, should be used preferentially over loop diuretics, which increase it [59]. If hypoparathyroidism is present, recombinant human parathyroid hormone (rhPTH, Natpara), commercially available in the United States, may be indicated.

Since ATP is comprised of three high-energy phosphate groups, impaired ATP and energy generation, leading to muscle weakness, is a consequence of hypophosphatemia. Other signs and symptoms, which typically only appear when the deficiency is severe, include bone pain and loss of bone density, hemolysis, cardiac and respiratory failure and rhabdomyolysis.

The general recommendation is to correct severe hypophosphatemia (phosphate levels <0.32 mmol/L) in symptomatic patients with the proviso that iv repletion may induce a life-threatening hypokalemia [64]. Moderate hypophosphatemia is treatable with oral supplementation of phosphate bearing in mind that active vitamin D is required for intestinal absorption. Typical oral supplementation amounts are three times the normal daily intake, with advised amounts of 2.5–3.5 g (80–110 mmol) per day, divided over two to three doses. (Fig. 6).

Hyponatremia, a serious electrolyte disorder associated with life-threatening neurological complications, is defined as a decrease in serum concentration of sodium, the major extracellular cation <136 mEq/L due to an excess of water relative to solute [65]. Serum sodium (Na⁺) concentration is tightly regulated principally by the antidiuretic actions of arginine vasopressin (AVP), which binds to the V2 receptor in the renal collecting ducts [66] and stimulates translocation of the aquaporin-2 water channels, resulting in increased free-water reabsorption [67]. The mineralocorticoid hormone, aldosterone, also regulates sodium (and potassium) levels via the amiloride‐sensitive sodium channel and Na–K ATPase pump [68].

Platinum chemotherapy has been associated with both renal salt-wasting syndrome (RSWS) and inappropriate antidiuretic hormone secretion (SIADH [69]). Since the treatment for RSWS is supplement of salt, while SIADH requires fluid restriction, it is important to make the distinction. The incidence of platinum-induced hyponatremia may be as high as 43% [70].

The mechanism by which platinum chemotherapy leads to renal salt wasting is not well understood. Platinum-induced nephrotoxicity is related to accumulation [71, 72] in the proximal and distal epithelial cells (however, it preferentially targets the proximal cells [73]) with subsequent inflammation, functional alteration of cell membrane transporters and apoptosis. Therefore, the most likely site for depressed renal sodium absorption in RSWS is the proximal nephron where the bulk of filtered Na is reabsorbed. Decreased proximal reabsorption results in the delivery of greater amounts of sodium to the distal nephron; however, with platinum-mediated damage of the distal tubule [74], the expected compensatory distal increase in sodium transport is impaired or prevented, leading to net Na excretion.

In addition to direct renal tubular toxicity, platinum agents may also cause SIADH; however, several tumors including lung, breast and head and neck traditionally treated with platinum doublets are also associated with SIADH [75], which complicates the clinical picture.

The main clinical manifestations of renal salt-wasting syndrome are hyponatremia, increased urinary sodium, increased urine output and hypovolemia, while SIADH is characterized by hyponatremia, increased urinary sodium, normal urine output and euvolemia. Orthostatic hypotension or tachycardia, dry mucus membranes and poor skin turgor [76] as well as a high blood urea nitrogen (BUN) suggest volume depletion (hypovolemia), while a low BUN, normal skin turgor, moist mucus membranes and absence of orthostatic hypotension or tachycardia are supportive of euvolemia [77]. One potential clue to differentiate cancer-related SIADH from platinum-mediated RSWS is that the latter is more likely to be accompanied by other electrolyte abnormalities such as hypomagnesemia, hypokalemia, hypophosphatemia and hypocalcemia [70].

The distinction between the two clinical entities is not academic because the treatment of choice for RSWS is hypertonic saline supplementation, while for SIADH it is fluid restriction, which is detrimental and possibly even lethal for a patient with RSWS. As an alternative to fluid restriction, since adequate hydration is necessary to prevent nephrotoxicity in cisplatin-treated patients, a vaptan (antidiuretic hormone receptor antagonist, e.g., tolvaptan) may be trialed [78] (Table 5).

The mostly neurological symptoms associated with hyponatremia (e.g., headache, nausea, vomiting, lethargy, disorientation) are related to the fall in serum tonicity, which favors water movement into the brain, potentially resulting in cerebral edema. However, because the brain’s adaptive reaction to counteract the edema is extrusion of inorganic and organic solutes, a too rapid correction of the serum sodium (>0.5 mmol/L/h), especially when the hyponatremia has been present for >48 h, may result in a pathology called osmotic demyelination syndrome, which is characterized by motor abnormalities, mental state disturbances and coma [76, 79].