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Page 8 of 33 Berardi et al. J Cancer Metastasis Treat 2019;5:79 I http://dx.doi.org/10.20517/2394-4722.2019.008

Table 2. Causes of hypernatremia
Causes of hypernatremia
Euvolemic: loss of free water Losses through skin and breath
Reduced thirst stimulation
Neurogenic or nephrogenic diabetes insipidus
Hypovolemic: loss of free water Renal disorders (diuretics, tubular necrosis)
Gastro-intestinal disorders (e.g., vomiting, nasogastric drainage, entero-cutaneous fistulae, diarrhea)
Cutaneous diseases (burns, excessive sweating)
Hypervolemic: sodium Hypertonic sodium bicarbonate or hypertonic saline infusion
accumulation Excessive ingestion of NaCl
Use of emetics rich in NaCl
Enteral nutrition
Urogenital injection of hypertonic saline
Hypertonic dialysis
Primitive hyperaldosteronism
Cushing Syndrome

Causes
In cancer patients, several causes might induce hypernatremia [Table 2] [51,52] :
(1) Cancer: anorexia and cancer cachexia, kidney damage, brain metastasis inducing diabetes insipidus,
and gastrointestinal disorders due to cancer infiltration (e.g., fistulae and nasogastric drainage due to bowel
obstruction) can induce hypernatremia.

(2) Cancer treatment: adverse events such as vomiting and diarrhea common to most anti-cancer agents
(chemotherapy, TKIs, and immunotherapies) associated with reduced thirst stimulation might cause
hypernatremia. Elevated serum sodium concentration might be induced also by bowel direct damage
due to antiangiogenetic agents or immunotherapy. Furthermore, some chemotherapeutic agents such as
ifosfamide might induce an iatrogenic diabetes insipidus.

(3) Concomitant drugs: osmotic diuretics, corticosteroids, enteral or parenteral nutrition, and hypertonic
saline infusion can induce hypernatremia.

(4) Concomitant diseases: cushing syndrome might induce hypernatremia.

Two different basic mechanisms might be involved in hypernatremia development: water loss (for reduced
introduction (euvolemic hypernatremia) or increased elimination (hypovolemic hypernatremia), or, rarely,
accumulation of sodium (often on iatrogenic basis, hypervolemic hypernatremia). Understanding these
mechanisms is crucial for a correct differential diagnosis among potential causes of hypernatremia.

The most frequent mechanism underlying hypernatremia is total body water loss due to impaired thirst
stimulation. It is often associated with altered mental status conditions, such as older age, brain tumors,
damage, or surgery, causing a deficit in thirst and osmoregulation . Water loss can also be due to renal or
[51]
[52]
extra renal disorders .
Renal water loss usually is caused by osmotic diuresis (e.g., hyperglycemia, increased serum urea
[53]
concentration, or administration of mannitol or hypertonic solutions) and by a treatment with diuretics .
Rarely, renal water loss can be induced by insipidus diabetes, a deficit of the vasopressin-ADH-receptor
system, which can have a central or a nephrogenic origin. Central insipidus diabetes is characterized by a
reduced secretion of AVP, often related to a central nervous system damage (e.g., pituitary or hypothalamus
[54]
neoplasms, brain surgery, or irradiation) . Nephrogenic insipidus diabetes instead depends on renal
resistance to the action of AVP. It is a rarely congenic condition, more frequently related to iatrogenic effect
[53]
of amphotericin B, lithium, ifosfamide, foscarnet, and streptozocin on tubular reabsorption of water .