Causes of Dysnatremia in Cancer Patients: A Review

Dysnatremias occur with high incidence in cancer patients and have negative impact on quality of life, survival, hospitalization length. Both cancer and its therapy are responsible; coexisting comorbidities may also be involved. Hyponatremia is the most common electrolyte disorder and is usually multifactorial. Hypernatremia, although more rare, is associated with poorer outcome. Diagnosis of true dysnatremias may be a challenge in patients with active cancer, as they must be often differentiated from spurious dysnatremias. Assessing the extracellular volume is the first step for establishing the cause of a dysnatremia; as such hypovolemic, euvolemic and hypervolemic dysnatremias have distinct etiology. The present article briefly reviews cancer-specific and treatment-specific causes of dysnatremias.


INTRODUCTION
Nephrologists are frequently confronted with dyselectrolytemia in cancer patients, both in acute settings or in ambulatory consultations. Cancer itself, side effects of conventional chemotherapy and of newer anticancer therapies, acute kidney injury or chronic kidney

Mini-review Article
disease, malnutrition and comorbid conditions and their treatment are all potential drivers of electrolyte disorders. Quite often more than one electrolyte disorder is noted in cancer patients. Dyselectrolytemia has negative impact on quality of life, survival, and length of hospitalization. It also negatively influences the timing of anticancer treatment initiation.
In a recent study on 1,088 patients with various neoplasms enrolled in phase 1 trials, most of them (1,044) without renal dysfunction, an electrolyte panel performed before beginning therapy revealed an increased incidence of dyselectrolyemia: 62% had hyponatremia, 40% hypokalemia, 32% hypophosphataemia, 17% hypomagnesaemia and 12% hypocalcemia [1]. The same study also showed that patients with high-grade dyselectrolytemia had a survival 1.61 times lower compared to other patients (without electrolyte disorders or low-grade) [1].
Acute kidney injury is the source of most lifethreatening acute and complex electrolyte disorders in the neoplastic patients [2]. In a study of 25,881 patients with various neoplasms, 79% of whom had acute kidney injury, 58% had at least one electrolyte or acid-base disorder; 27.8% of patients had hypocalcemia, 26.7% hypophosphataemia, 22.5% hyponatremia [3]. The same study showed that the mortality of patients with electrolyte disturbances was 7 times higher than those without electrolyte disturbances, and the duration of hospitalization was 3 times longer [3].

DYSNATREMIAS
Dysnatremias are the most common electrolyte disturbances in cancer patients and represent major cause for nephrology consultations. Normal serum sodium has a range between 135 to 145 mEq/L, hyponatremia being defined as serum sodium less than 135 mEq/L and hypernatremia as serum sodium higher than 145 mEq/L. Both hyponatremia and hypernatremia are noted with increased incidence in cancer and the clinicians must differentiate pseudodysnatremias from real sodium disturbances before exploring the cause and recommend a treatment (Fig. 1).

Pseudohyponatremia
(a serum sodium concentration of less than 135 mEq/L in the setting of a normal serum osmolality) may be present due to increased serum lipid concentrations (hypertriglyceridemia, hypercholesterolemia) or in case of abnormal high serum levels of proteins (malignant monoclonal gammopathies, such as multiple myeloma; hypergammaglobulinemia; malignant lymphoproliferative disorders; immunoglobulin deposition diseases, such as amyloidosis; intravenous immunoglobulin therapy, etc) [4,5].
Pseudohypernatremia (false increase of serum sodium above 145 mEq/L) is noted in case of decreased serum levels of proteins [6,7]. As patients with cancer are prone to protein malnutrition, pseudohypernatremia may be more frequent than pseudohyponatremia, especially in advanced stages of cancer and in critically ill patients admitted to intensive care units.
Pseudonormonatremia is defined as a falsely normal sodium levels in the presence of predisposing factors for dysnatremia [6,7]. As such, a normal value of serum sodium must draw attention to a real hyponatremia in the case of a patient with increased serum lipids or proteins. Alternatively, if serum sodium is normal in a patient with hypoalbuminemia, there is a high probability that real value of sodium is higher than normal.
For differentiation of spurious dysnatremia from a real sodium disturbance, clinicians must be aware of both method of dosing serum sodium and also presence of serum abnormalities in a patient (serum levels of albumin, presence of abnormal proteins, serum levels of cholesterol and triglycerides). Regarding the method of measuring serum sodium, it is important to know if a direct ion-selective electrodes method is usedin this case the results from the laboratory are true, or an indirect method is used in this case corrections of the results are necessary [8].

CAUSES OF HYPONATREMIA IN CANCER
Hyponatremia is the most common electrolyte disturbance in patients with neoplasms [9]. The etiology of hyponatremia in cancer is very heterogeneous (Table 1) and the most frequent neoplasia associated with hyponatremia is small cell lung cancer which is highly associated with syndrome of inappropriate antidiuretic hormone (ADH) secretion (SIADH) [10]. From the management point of view, it is important to classify hyponatremia as hypovolemic, normovolemic and hypervolemic. (Table 1).

Fig. 1. Differentiating pseudodysnatremias from genuine dysnatremias
Legend: ECV=extracellular volume Hypovolemic hyponatremia: Occurs in more than 1/3 of cancer patients [8] and is often secondary to increased water and salt loss from vomiting and/or diarrhea following cytostatic regimens. However, increased gastrointestinal losses can also occur secondary to the extension of digestive neoplasms (bowel obstructions, peritonitis, gastrointestinal bleeding, etc.), in acute or chronic uremia, etc. Increased renal losses of salt and water may cause hypovolemic hyponatremia; they may occur after some chemotherapeutics such as cisplatinium which has a direct toxic tubular effect [11], after increased doses of diuretic or in the context of brain metastases in which the kidney-hypothalamus axis is interrupted [12]. Rare causes like paraneoplastic atrial natriuretic peptide or brain natriuretic peptide secretion may also be accompanied by renal salt wasting.
Euvolemic hyponatremia: Is caused in most cancer patients by SIADH. SIADH is a syndrome characterized by an inappropriately increased secretion or action of antidiuretic hormone in the presence of a normal plasma osmolality. Increased water reabsorption in the renal collecting tubules as a result of ADH action is accompanied by an initial increase in extracellular volume and dilutional hyponatremia; as a consequence of initial hypervolemia, decreased sodium and water reabsorption occur in renal tubules with correction of extracellular volume status, but with aggravating hyponatremia. Cancer-related SIADH may arise by several mechanisms: -ectopic secretion of ADH from tumor cells is most often noted in bronchogenic small cell carcinoma (up to more than 40% of the patients), but it has been also reported in head and neck neoplasms and in some hematologic cancers [13][14][15].
-enhancing the effect of ADH may be noted after cyclophosphamide, non-steroidal antiinflammatory drugs or anticonvulsants [16].
Hypervolemic hyponatremia: Is characterized by an excess of free water in the body. It may occur after increased water intake especially when associated with low-sodium diet and other predisposing condition like treatment with cyclophosphamide. More often in clinical practice hypervolemic hyponatremia is a consequence of congestive heart failure (coexisting or caused by cardiotoxic chemotherapeutics), nephrotic syndrome, decompensated cirrhosis or oliguric stage of acute kidney injury or advanced stages of chronic kidney disease [16,18].

CAUSES OF HYPERNATREMIA IN CANCER
In contrast with hyponatremia, true hypernatremia, defined by an increase in serum sodium above 145 mEq/L, is rare in cancer patients, reported in less than 3% of patients [19], but, also compared with hyponatremia, it is associated with higher mortality and hospitalization length [19]. More often cancer patients present with factitious hypernatremia secondary to hypoalbuminemia especially in advanced stages [6].
Presence of hypernatremia denotes reduced water intake, free water loss, or increased sodium intake. Assessing extracellular volume status is important for classification of hypernatremia: hypovolemic, euvolemic or hypervolemic ( Table 2).
Hypovolemic hypernatremia: Can occur secondary to predominant water losses or to reduced water intake, especially when associated with a normal or high sodium diet. The general causes of hypovolemic hypernatremia which are frequently reported in neoplasms are gastrointestinal water losses (vomiting / diarrhea after cytostatics, abdominal neoplasms complicated by enteric-cutaneous fistulas, prolonged nasogastric aspiration without parenteral replacement of losses, etc.). Renal water losses may be responsible of hypovolemic hypernatremia during recovery stage of AKI, after increased parenteral doses of mannitol or during severe hyperglycemia (osmotic diuresis) [20]. Enteral nutrition with hyperproteic solutions may also induce hypovolemic hypernatremia if is not associated with enteral or parenteral fluid supplementation [21].
Euvolemic hypernatremia: Occurs frequently after reduced oral water intake especially in patients with brain tumors, brain metastases or in the context of advanced age. Decreased fluid intake may also occur secondary to reduced appetite or due to esophagitis, mucositis, or nausea after some chemotherapeutics. Euvolemic hypernatremia is a feature of central diabetes insipidus (low ADH secretion) occurring in primary or metastatic tumors of the pituitary gland or hypothalamus, after ablative surgery of these tumors or secondary to whole brain radiation in patients with central nervous system lymphomas or brain tumors [22,23]. In some of these patients, lesions involving hypothalamic osmoreceptors may lead to reduced thirst and decreased water intake with severe dehydration, a dangerous and rare syndrome called adipsic diabetes insipidus [24,25]. Some chemotherapeutics may interfere with the renal action of ADH by inducing nephrogenic diabetes insipidus; the most commonly involved are amphotericin B, ifosfamide, platinum derivatives [26].
Hypervolemic hypernatremia: Is most often an iatrogenic disorder: excessive parenteral administration of hypertonic sodium chloride or sodium bicarbonate solutions; it rarely occurs due to increased oral salt intake [20].

CANCER THERAPY-RELATED DYSNATREMIA
Anticancer therapy is recognizing a major diversification in the last decades and, in parallel with higher remission rates of neoplasms and improved survival rate of the patients, several side-effects are increasingly noted. Dysnatremias are associated with both conventional and novel cancer therapies and the same drug may act by different mechanisms in producing a sodium disturbance (Table 3) [2,27]. In order to search the mechanism for drugrelated dysnatremia, the first step is, as stipulated above, to establish the extracellular volume status in each patient. Moreover, as a lot of cancer therapies may induce acute kidney injury through direct tubular toxicity, by acute allergic tubulointerstitial nephropathies or by thrombotic microangiopathy, assessment of kidney function is mandatory for establishing the etiology of dysnatremias [2].

RENAL-DYSFUNCTION ASSOCIATED DYSNATREMIAS
Dysnatremias are specific features of kidney dysfunction, either acute or chronic where they are usually accompanied by other electrolyte disturbances [2,3].  Cancer patients are at increased risk for acute kidney injury secondary to cancer extension, medication or coexisting diseases [2]. Hypovolemic hyponatremia of various etiologies may itself complicate with acute tubular necrosis if left untreated. Hypervolemic hyponatremia (dilutional hyponatremia) is a common feature of oliguric stage of acute kidney injury, being often indication for emergency dialysis. In patients recovering from acute kidney injury and evolving with marked polyuria, hypovolemic hyponatremia or hypovolemic hypernatremia may develop, depending the oral fluid intake or type of parenteral solutions used for replacement.
Chronic kidney disease is also noted with increased prevalence in cancer patients [28]. Besides dysnatremias secondary to impaired of both urine concentration and dilution abilities, overdosing of kidney-excreted chemotherapeutics may be noted and therefore augmented dysnatremic side-effects.

ENDOCRINE-RELATED DYSNATRE-MIAS IN CANCER PATIENTS
Although rare, endocrine causes of dysnatremias must not be neglected in selected patients. Patients with thyroid cancer, those with primary or metastatic adrenal cancer, patients with hypothalamus or pituitary gland malignancies or patients undergoing brain radiation or brain surgery are at increased risk for dysnatremias by various mechanisms.
Moreover, there are situations in which a lesion associates either hyponatremia or hypernatremia. Best examples are hypothalamic or/and pituitary tumors (primary or metastatic) which may manifest either with hyperfunction, or with hypofunction, ie with increased secretion of ADH (= SIADH) or decreased secretion of ADH (= diabetes insipidus); whole brain radiation or surgical removal of the tumors in these sites are always associated with low ADH secretion [17,22,29].
Primary adrenal insufficiency (Addison's disease) resulting from adrenal primary cancer or metastases is usually associating hyponatremic hypovolemia as a result of salt and water losses induced by reduced secretion of aldosterone [29]. Secondary adrenal insufficiency after hypothalamus or pituitary injury (cancer, radiation) usually is not associated with abnormal secretion of aldosteron and patients present with euvolemic hyponatremia in the context of hypocortisolisminduced increased secretion of ADH (=SIADH) [29].
Hypothyroidism, especially severe and in rapid onset, like after radioactive iodine therapy and thyroidectomy in thyroid cancer [30] may associate euvolemic hyponatremia in context of SIADH secondary to decreased cardiac output and decreased glomerular filtration rate [31].

CONCLUSIONS
Dysnatremias are noted with high incidence in cancer patients, have heterogeneous etiology and are often multifactorial. Detailed history and laboratory assessment are necessary to establish the cause of sodium disturbances. Assessing the kidney function and extracellular volume status is mandatory for a precise diagnosis and management. Differentiating true from factitious dysnatremias is often required in clinical practice in cancer patients.

DISCLAIMER
The products used for this research are commonly and predominantly use products in our area of research and country. There is absolutely no conflict of interest between the authors and producers of the products because we do not intend to use these products as an avenue for any litigation but for the advancement of knowledge. Also, the research was not funded by the producing company rather it was funded by personal efforts of the authors.

CONSENT
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ETHICAL APPROVAL
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