Potassium disorders - Clinical Tree

Introduction

Potassium abnormalities, both hypo- and hyperkalemia, can occur with significant consequences in patients with malignancies. In addition to typical causes of disturbances in potassium homeostasis, there are unique etiologies within this special cohort including anticancer agent-induced disturbances on potassium excretion, direct effects of malignancies on cellular potassium release or uptake and potassium excretion by the kidneys, as well as artefactual changes more frequently seen in cancer. As the nature of potassium disturbances differ, it is imperative for management strategies to take into account these differences. For example, the clinical entity of tumor lysis syndrome (TLS) (described elsewhere in this text and in Chapter 30 ) may lead to a prolonged period of intracellular potassium release and potential reduction in potassium excretion if acute kidney injury (AKI) develops. As such, typical short-term hyperkalemia strategies of “stabilize, shift, excrete” used for single episodes may be ineffective. Conversely, chemotherapy-induced proximal tubular damage may lead to prolonged electrolyte wasting, necessitating high doses of potassium and magnesium replacement. Knowledge of the underlying nature of potassium abnormalities in cancer allows the clinician to devise more effective and appropriate treatment plans.

Risk of potassium disturbances in cancer

The risk of a particular patient experiencing potassium disorders during the course of therapy is dependent upon multiple factors including: cancer type and disease burden; cell turnover rate; exposure to anticancer agents associated with electrolyte abnormalities; underlying comorbidities, such as chronic kidney disease (CKD), which may predispose a patient to AKI; and adjunctive therapies, such as nonsteroidal antiinflammatories or antimicrobial agents, which may also induce electrolyte abnormalities. Prevalence of potassium abnormalities among cancer patients is variable depending upon type of cancer, underlying comorbidities and acuity level of the patient—a proxy for risk of worsening renal function/AKI. One review of hypokalemia in hospitalized patients demonstrated that patients with hematologic malignancies were the third most common group to suffer hypokalemia. Hypokalemia is more frequently encountered in the medical literature because of its well-known association with malignancies, such as acute myelogenous leukemia (AML) and in the setting of chemotherapy-induced tubular damage and excessive kaliuresis. Hyperkalemia is more often encountered in the setting of AKI or in connection with the TLS, or more rarely, adrenal-axis suppression. One small study of more than 600 patients, admitted to a dedicated cancer ward, demonstrated a total of around 2% prevalence of any potassium abnormality, with hypokalemia twice as likely to occur in a broad sample of malignancies. Given the interdisease variability, it is best to consider the risk of potassium abnormalities by patient-related factors and disease-related factors. Whereas solid tumors may be less likely to predispose a patient to potassium disturbances, more than 50% of patients with acute leukemia may suffer multifactorial hypokalemia.

Hypokalemia

Hypokalemia is commonly encountered in cancer patients. Although there are various definitions of hypokalemia, a widely accepted lower limit for a normal potassium concentration is 3.5 mmol/L. A serum potassium concentration of 2.5 to 3.0 mmol/L is considered moderate and a level less than 2.5 mmol/L is regarded as severe hypokalemia. Although the exact prevalence has not been evaluated in large cohorts of cancer patients, one large study showed the rate of hypokalemia to be 12% among hospitalized patients. Hypokalemia was largely of multifactorial etiology, with hematologic malignancy (9%) being a common causative factor. Concomitant hypomagnesemia occurred in 61% of patients. In another cohort of hospitalized patients, hypokalemia was observed in 16.8% of all first-time admissions, and malignancy was noted to be an independent risk factor for hospitalization with hypokalemia. A larger analysis of hospitalized patients revealed that 21% of hospitalized patients developed hypokalemia, with a strong association with malignancy, especially hematologic and gastrointestinal (GI) tract malignancy.

Etiologies

Hypokalemia may result from one of four possible etiologies: pseudohypokalemia; redistribution between cellular compartments; GI losses; and renal losses. In addition, hypomagnesemia is strongly associated with hypokalemia in malignancy, and contributes to kidney losses. Chemotherapy-induced decreased appetite and oral intake further confounds hypokalemia resulting from these losses. Typically, the etiology in cancer patients is largely “multifactorial,” and is summarized in Table 3.1 .

Table 3.1

Causes and Mechanisms of Hypokalemia in Cancer Patients

Modified from Bowman BT (2017). Electrolyte disorders associated with cancer. J Onconephrology , 1, 30–35.

Source of Potassium Loss	Cause	Mechanism
Renal losses	Acute myelogenous leukemia Chemotherapy agents: cisplatin/ifosfamide EGFR inhibitors: cetuximab and panitumumab BRAF/MEK inhibitors: vemurafenib and dabrafenib with trametinib	Lysozymuria (M4/M5) Renin secretion Fanconi syndrome/tubular toxicity Hypomagnesemia/tubular toxicity Fanconi syndrome/tubular toxicity
GI losses	Diarrhea/radiation enteritis/GI tumors	Intestinal/colonic BK potassium channel upregulation
Transcellular shifts	Myelopoietic agents Alkalosis	Potassium uptake in rapidly proliferating cells Induced from chemo-associated vomiting or alkaline hydration protocols

BK , Large-conductance calcium-activated potassium channels; EGFR , epidermal growth factor receptor; GI , gastrointestinal.

Workup and diagnosis of “true” hypokalemia are warranted after exclusion of pseudohypokalemia. The most common cause of pseudohypokalemia is acute leukemia, in which there are postphlebotomy transcellular shifts in the large number of abnormal leukocytes, if blood is stored in collection vials for prolonged periods, at room temperature. Rapid separation of plasma and storage at 4°C limits this issue.

Transcellular shifts of potassium in cancer patients are associated with malignancy-related medications and their adverse effects. Metabolic alkalosis from chemotherapy-induced vomiting, as well as alkaline volume expansion protocols, cause potassium to move intracellularly, as well as increased aldosterone activity resulting in increased potassium losses by the kidney. In addition, use of myelopoietic growth factors is associated with increased hematopoietic cell production, followed by rapid potassium uptake in the new cells. Similarly, increased production of blast cells in AML can also lead to hypokalemia.

GI losses in malignancy are largely caused by diarrhea that may occur because of chemotherapy, or radiation enteritis. Less commonly, villous adenoma or vasoactive intestinal secreting tumor (VIPoma) are associated with prolonged diarrhea and hypokalemia. ^, In addition, certain conditions in malignancy are associated with hypokalemia, secondary to upregulation of colonic/intestinal large-conductance calcium-activated potassium (BK) channels. ^, Hypokalemia associated with upper GI losses from vomiting or nasogastric suctioning is minimal, given the low (5–10 mEq/L) concentration of potassium in gastric secretions. The resulting hypokalemia is secondary to a combination of hypovolemia-induced aldosterone release, and increased bicarbonate delivery to the cortical collecting duct. The net effect is increased potassium secretion and urinary potassium wasting.

Potassium losses by the kidney in malignancy are associated with specific cancers and therapeutic agents and will be discussed in detail in the following sections. In addition, it is important to understand the mechanism of hypokalemia with concomitant hypomagnesemia, as it is frequently encountered in hypokalemia of malignancy. Luminal potassium secretion in the cortical collecting duct occurs via apical renal outer medullary potassium (ROMK) channels. Under physiologic conditions, intracellular magnesium binds ROMK and blocks potassium secretion. An increase in ROMK activity from magnesium deficiency (low intracellular magnesium) releases the magnesium-mediated inhibition of ROMK channels and increases potassium secretion. Additional factors for potassium secretion (distal sodium delivery, increased aldosterone levels) are essential for exacerbating potassium wasting and hypokalemia in magnesium deficiency ( Fig. 3.1 ). Hypomagnesemia in cancer patients may be caused by decreased intake or from increase urinary magnesium wasting. Losses of magnesium by the kidney are largely caused by chemotherapy-mediated injury to the distal nephron.

Fig. 3.1, K + secretion by principal cells. The basolateral Na + K + ATPase lowers intracellular Na + concentration, and increases K + concentration. Entry of Na + via ENaC channels depolarizes the apical membrane, resulting in K + efflux via luminal ROMK channels. Flow-induced increases in K + secretion is mediated by BK channels. BK , Large-conductance calcium-activated potassium channels; ENaC , epithelial sodium channel; K + , potassium; Na + , sodium; ROMK , renal outer medullary potassium.

Hypokalemia associated with specific cancers

Among hematologic malignancies, hypokalemia is the most pronounced electrolyte abnormality in acute leukemia. Hypokalemia has been primarily described in patients with monocytic (M4) and acute myelomonocytic (M5) subtypes. It is mainly attributed to lysozymuria-induced renal tubular injury with kaliuresis. ^, ^, Lysozyme is an enzyme originating from blood granulocytes and monocytes, as well as tissue macrophages. Lysozyme is normally reabsorbed in the proximal convoluted tubule. Lysozymuria occurring in patients with leukemia has been attributed to proliferation and destruction of lysozyme containing cells. Filtered lysozyme appears to be a direct tubular toxin. In addition, high levels of tubular lysozyme may induce significant kaliuresis and hypokalemia. Lysozymuria leading to profound hypokalemia has also been reported in chronic myelogenous leukemia. There have also been reports of renin-like activity in leukemic cells, stimulating the mineralocorticoid pathways and increasing potassium secretion by the kidney. ^,

Additional cancer-specific disorders associated with hypokalemia include disorders of mineralocorticoid excess. Although most adrenal adenomas are nonfunctional, up to 15% can be functional, secreting increased amounts of cortisol, which overwhelm 11-beta-hydroxysteroid dehydrogenase’s ability to metabolize cortisol to cortisone. Thus cortisol is able to bind the mineralocorticoid receptor and stimulate potassium excretion via ROMK channels ( Fig. 3.2 ). Adrenal carcinomas are rare and present with signs and symptoms of elevated cortisol levels. ^,

Fig. 3.2, K + secretion with adrenal adenomas. Cortisol activates the mineralocorticoid receptor, resulting in increased ENaC, and subsequent ROMK activity. 11 β HSD converts cortisol to cortisone, which does not have mineralocorticoid activity. Increased amounts of cortisol exceed the ability of 11 β HSD to metabolize cortisol. Aldo , Aldosterone; ENaC , epithelial sodium channel; K + , potassium; MR , mineralocorticoid receptor; Na + , sodium; ROMK , renal outer medullary potassium; 11 β HSD , 11 beta hydroxyl steroid dehydrogenase.

Proximal tubular toxicity resulting from κ light chain myeloma, resulting in Fanconi syndrome is an indirect cause of malignancy associated hypokalemia. In dysproteinemias, the degree of filtered light chains exceeds the proximal tubule’s resorptive capacity, resulting in light chain proteinuria. Proximal tubule endocytosis of these light chains results in intracellular oxidative stress and cell apoptosis. The resulting proximal tubular disorder is Fanconi syndrome, with bicarbonaturia, glycosuria, aminoaciduria, phosphaturia, hyperuricosuria, and potassium wasting. Hypokalemia in proximal renal tubular acidosis results primarily in cases of supplemental bicarbonate repletion.

Other rare causes of cancer-specific hypokalemia include ectopic adrenocorticotropic hormone (ACTH) producing tumors. These include small-cell lung cancer, bronchial carcinoid tumors, lung adenocarcinomas, thymic tumors, pancreatic tumors and medullary thyroid cancer. Up to 30% of ectopic ACTH syndrome may present as occult tumors.

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