Hyponatremia and MAP‐kinase inhibitors in malignant melanoma: Frequency, pathophysiological aspects and clinical consequences

Abstract

The incidence of malignant melanoma has increased over the past two decades. A combined BRAF/MEK inhibitor regimen has been shown to lead to prolonged survival and progression‐free survival in patients with metastatic BRAF V600‐mutant melanoma. Different nephrotoxic effects have been described, among them hyponatremia. The goal of the present narrative review was to understand the pathophysiological mechanisms driving hyponatremia when using selective BRAF inhibitors and/or MEK inhibitors in order to propose potential strategies to prevent or to treat this side effect. Several mechanisms of kidney injury have been suggested including changes in glomerular and tubular function. However, the precise mechanisms of hyponatremia remain unknown. Our hypothesis is that BRAF/MEK inhibitors lead to hyponatremia and water retention (so‐called dilution hyponatremia) by activating aquaporin 2 (AQP2) trafficking from its intracellular compartment to the luminal cell membrane, and by activating ENaC channel. Therefore, we recommend treating the hyponatremia related to BRAF/MEK inhibitors with restriction of fluid intake.

Hyponatremia in the cancer patient

“…82 The new v-Raf murine sarcoma viral oncogene homolog B (BRAF)/mitogen-activated protein kinase kinase enzyme (MEK) inhibitors might lead to hyponatremia by stimulating aquaporin 2 trafficking to the apical membrane of the collecting duct cells. 83,84 Selinexor, a recently approved agent used in the treatment of multiple myeloma, has a strong association with hyponatremia (unclear mechanism), with an incidence ranging from 7% to 26%. 85 Other medications used in the context of cancer care, such as antidepressants (e.g., selective serotonin reuptake inhibitors), antiepileptics (e.g., carbamazepine), and opiates are also commonly associated with SIAD.…”

Trametinib-associated Hyponatremia in a Child With Low-grade Glioma is Not Seen Following Treatment With Alternative MEK Inhibitor

“…Hyponatremia has been reported in adult patients treated with a combination of MEK inhibitors and BRAF inhibitors for BRAF V600 -mutant metastatic melanoma or non-small cell lung cancer, 11 but little is known about the risk of hyponatremia with MEK inhibitor monotherapy in children. The incidence of grade 3/4 hyponatremia (sodium <130 mmol/L, as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events [CTCAE], version 4.0) in phase II/III trials of BRAF/MEK inhibitor combination therapy in adults ranged from 2% to 17% (2% to 6% with vemurafenib/cobimetinib, 4% with encorafenib/binimetinib, and 6% to 17% with dabrafenib/ trametinib) 11,14,15 ; however, studies evaluating single-agent MEK inhibitor (trametinib) treatment in adult patients have not identified hyponatremia as a potential adverse event. 16 Severe hyponatremia has been described in 2 pediatric patients with progressive hypothalamic/chiasmatic LGGs with known diabetes insipidus.…”

“…Prior reports have proposed upregulation of aquaporin channels as a potential mechanism to explain hyponatremia associated with trametinib use as well as other MEK inhibitorspecific toxicities. 11,12 Emerging evidence suggests expression of aquaporin-2 channels in the kidneys is mediated by the MAPK pathway, 18,19 such that MEK inhibition may result in increased trafficking of aquaporin-2 channels to the apical membrane of the renal tubule, 11 leading to water retention and hyponatremia, in a manner similar to syndrome of inappropriate antidiuretic hormone. Our patient's labs obtained at the time of severe hyponatremia are consistent with this explanation, with low serum osmolality, high urine osmolality, and increased urinary sodium, all of which returned to normal ranges following discontinuation of trametinib.…”

“…[3][4][5] Rare but serious complications to the heart, retina, and other organ systems can also occur and require additional surveillance. [6][7][8][9] While electrolyte abnormalities such as hyponatremia have been described among adult patients treated with a combination of MEK inhibitors and BRAF inhibitors, 10,11 only 1 pediatric case series reports hyponatremia with trametinib monotherapy in 2 patients with diabetes insipidus. 12 Herein, we describe hyponatremia associated with trametinib therapy in a pediatric patient with a progressive LGG with no underlying endocrinopathy, and resolution of this toxicity after switching to a different MEK inhibitor agent.…”

“…Rare but serious complications to the heart, retina, and other organ systems can also occur and require additional surveillance 6–9. While electrolyte abnormalities such as hyponatremia have been described among adult patients treated with a combination of MEK inhibitors and BRAF inhibitors,10,11 only 1 pediatric case series reports hyponatremia with trametinib monotherapy in 2 patients with diabetes insipidus 12…”