Homeostatic mechanisms maintain plasma K+ concentration between 3.5 and 5.0 mM, despite marked variation in dietary K+ intake. In a healthy individual at steady state, the entire daily intake of potassium is excreted, approximately 90% in the urine and 10% in the stool; thus, the kidney plays a dominant role in potassium homeostasis. However, more than 98% of total-body potassium is intracellular, chiefly in muscle; buffering of extracellular K+ by this large intracellular pool plays a crucial role in the regulation of plasma K+ concentration. Changes in the exchange and distribution of intra- and extracellular K+ can thus lead to marked hypo- or hyperkalemia. A corollary is that massive necrosis and the attendant release of tissue K+ can cause severe hyperkalemia, particularly in the setting of acute kidney injury and reduced excretion of K+. Show Changes in whole-body K+ content are primarily mediated by the kidney, which reabsorbs filtered K+ in hypokalemic, K+-deficient states and secretes K+ in hyperkalemic, K+-replete states. Although K+ is transported along the entire nephron, it is the principal cells of the connecting segment (CNT) and cortical CD that play a dominant role in renal K+ secretion, whereas alpha-intercalated cells of the outer medullary CD function in renal tubular reabsorption of filtered K+ in K+-deficient states. In principal cells, apical Na+ entry via the amiloride-sensitive ENaC generates a lumen-negative potential difference, which drives passive K+ exit through apical K+ channels (Fig. 63-4). Two major K+ channels mediate distal tubular K+ secretion: the secretory K+ channel ROMK (renal outer medullary K+ channel; also known as Kir1.1 or KcnJ1) and the flow-sensitive big potassium (BK) or maxi-K K+ channel. ROMK is thought to mediate the bulk of constitutive K+ secretion, whereas increases in distal flow rate and/or genetic absence of ROMK activate K+ secretion via the BK channel. An appreciation of the relationship between ENaC-dependent Na+ entry and distal K+ secretion (Fig. 63-4) is required for the bedside interpretation of potassium disorders. For example, decreased distal delivery of Na+, as occurs in hypovolemic, prerenal states, tends to blunt the ability to excrete K+, leading to hyperkalemia; on the other hand, an increase in distal delivery of Na+ and distal flow rate, as occurs after treatment with thiazide and loop diuretics, can enhance K+ secretion and lead to hypokalemia. Hyperkalemia is also a predictable consequence of drugs that directly inhibit ENaC, due to the role of this Na+ channel in generating a lumen-negative potential difference. Aldosterone in turn has a major influence on potassium excretion, increasing the activity of ENaC channels and thus amplifying the driving force for K+ secretion across the luminal membrane of principal cells. Abnormalities in the renin-angiotensin-aldosterone system can thus cause both hypokalemia and hyperkalemia. Notably, however, potassium excess and potassium restriction have opposing, aldosterone-independent effects on the density and activity of apical K+ channels in the distal nephron, i.e., factors other than aldosterone modulate the renal capacity to secrete K+. In addition, potassium restriction and hypokalemia activates aldosterone-independent distal reabsorption of filtered K+, activating apical H+/K+-ATPase activity in intercalated cells within the outer medullary CD. Reflective perhaps of this physiology, changes in plasma K+ concentration are not universal in disorders associated with changes in aldosterone activity. HYPOKALEMIAHypokalemia, defined as a plasma K+ concentration of <3.5 mM, occurs in up to 20% of hospitalized patients. Hypokalemia is associated with a 10-fold increase in in-hospital mortality, due to adverse effects on cardiac rhythm, blood pressure, and cardiovascular morbidity. Mechanistically, hypokalemia can be caused by redistribution of K+ between tissues and the ECF or by renal and nonrenal loss of K+ (Table 63-4). Systemic hypomagnesemia can also cause treatment-resistant hypokalemia, due to a combination of reduced cellular uptake of K+ and exaggerated renal secretion. Spurious hypokalemia or “pseudohypokalemia” can occasionally result from in vitro cellular uptake of K+ after venipuncture, for example, due to profound leukocytosis in acute leukemia. TABLE 63-4Causes of Hypokalemia View Table||Download (.pdf) TABLE 63-4Causes of Hypokalemia
Redistribution and HypokalemiaInsulin, β2-adrenergic activity, thyroid hormone, and alkalosis promote Na+/K+-ATPase-mediated cellular uptake of K+, leading to hypokalemia. Inhibition of the passive efflux of K+ can also cause hypokalemia, albeit rarely; this typically occurs in the setting of systemic inhibition of K+ channels by toxic barium ions. Exogenous insulin can cause iatrogenic hypokalemia, particularly during the management of K+-deficient states such as diabetic ketoacidosis. Alternatively, the stimulation of endogenous insulin can provoke hypokalemia, hypomagnesemia, and/or hypophosphatemia in malnourished patients given a carbohydrate load. Alterations in the activity of the endogenous sympathetic nervous system can cause hypokalemia in several settings, including alcohol withdrawal, hyperthyroidism, acute myocardial infarction, and severe head injury. β2 agonists, including both bronchodilators and tocolytics (ritodrine), are powerful activators of cellular K+ uptake; “hidden” sympathomimetics, such as pseudoephedrine and ephedrine in cough syrup or dieting agents, may also cause unexpected hypokalemia. Finally, xanthine-dependent activation of cAMP-dependent signaling, downstream of the β2 receptor, can lead to hypokalemia, usually in the setting of overdose (theophylline) or marked overingestion (dietary caffeine). Redistributive hypokalemia can also occur in the setting of hyperthyroidism, with periodic attacks of hypokalemic paralysis (thyrotoxic periodic paralysis [TPP]). Similar episodes of hypokalemic weakness in the absence of thyroid abnormalities occur in familial hypokalemic periodic paralysis, usually caused by missense mutations of voltage sensor domains within the α1 subunit of L-type calcium channels or the skeletal Na+ channel; these mutations generate an abnormal gating pore current activated by hyperpolarization. TPP develops more frequently in patients of Asian or Hispanic origin; this shared predisposition has been linked to genetic variation in Kir2.6, a muscle-specific, thyroid hormone–responsive K+ channel. Patients with TPP typically present with weakness of the extremities and limb girdles, with paralytic episodes that occur most frequently between 1 and 6 am. Signs and symptoms of hyperthyroidism are not invariably present. Hypokalemia is usually profound and almost invariably accompanied by hypophosphatemia and hypomagnesemia. The hypokalemia in TPP is attributed to both direct and indirect activation of the Na+/K+-ATPase, resulting in increased uptake of K+ by muscle and other tissues. Increases in β-adrenergic activity play an important role in that high-dose propranolol (3 mg/kg) rapidly reverses the associated hypokalemia, hypophosphatemia, and paralysis. Nonrenal Loss of PotassiumThe loss of K+ in sweat is typically low, except under extremes of physical exertion. Direct gastric losses of K+ due to vomiting or nasogastric suctioning are also minimal; however, the ensuing hypochloremic alkalosis results in persistent kaliuresis due to secondary hyperaldosteronism and bicarbonaturia, i.e., a renal loss of K+. Diarrhea is a globally important cause of hypokalemia, given the worldwide prevalence of infectious diarrheal disease. Noninfectious gastrointestinal processes such as celiac disease, ileostomy, villous adenomas, inflammatory bowel disease, colonic pseudo-obstruction (Ogilvie’s syndrome), VIPomas, and chronic laxative abuse can also cause significant hypokalemia; an exaggerated intestinal secretion of potassium by upregulated colonic BK channels has been directly implicated in the pathogenesis of hypokalemia in many of these disorders. Renal Loss of PotassiumDrugs can increase renal K+ excretion by a variety of different mechanisms. Diuretics are a particularly common cause, due to associated increases in distal tubular Na+ delivery and distal tubular flow rate, in addition to secondary hyperaldosteronism. Thiazides have a greater effect on plasma K+ concentration than loop diuretics, despite their lesser natriuretic effect. The diuretic effect of thiazides is largely due to inhibition of the Na+-Cl– cotransporter NCC in DCT cells. This leads to a direct increase in the delivery of luminal Na+ to the principal cells immediately downstream in the CNT and cortical CD, which augments Na+ entry via ENaC, increases the lumen-negative potential difference, and amplifies K+ secretion. The higher propensity of thiazides to cause hypokalemia may also be secondary to thiazide-associated hypocalciuria, versus the hypercalciuria seen with loop diuretics; the increases in downstream luminal calcium in response to loop diuretics inhibit ENaC in principal cells, thus reducing the lumen-negative potential difference and attenuating distal K+ excretion. High doses of penicillin-related antibiotics (nafcillin, dicloxacillin, ticarcillin, oxacillin, and carbenicillin) can increase obligatory K+ excretion by acting as nonreabsorbable anions in the distal nephron. Finally, several renal tubular toxins cause renal K+ and magnesium wasting, leading to hypokalemia and hypomagnesemia; these drugs include aminoglycosides, amphotericin, foscarnet, cisplatin, and ifosfamide (see also “Magnesium Deficiency and Hypokalemia,” below). Aldosterone activates the ENaC channel in principal cells via multiple synergistic mechanisms, thus increasing the driving force for K+ excretion. In consequence, increases in aldosterone bioactivity and/or gains in function of aldosterone-dependent signaling pathways are associated with hypokalemia. Increases in circulating aldosterone (hyperaldosteronism) may be primary or secondary. Increased levels of circulating renin in secondary forms of hyperaldosteronism lead to increased angiotensin II and thus aldosterone; renal artery stenosis is perhaps the most frequent cause (Table 63-4). Primary hyperaldosteronism may be genetic or acquired. Hypertension and hypokalemia, due to increases in circulating 11-deoxycorticosterone, occur in patients with congenital adrenal hyperplasia caused by defects in either steroid 11β-hydroxylase or steroid 17α-hydroxylase; deficient 11β-hydroxylase results in associated virilization and other signs of androgen excess, whereas reduced sex steroids in 17α-hydroxylase deficiency lead to hypogonadism. The major forms of isolated primary genetic hyperaldosteronism are familial hyperaldosteronism type I (FH-I, also known as glucocorticoid-remediable hyperaldosteronism [GRA]) and familial hyperaldosteronism types II and III (FH-II and FH-III), in which aldosterone production is not repressible by exogenous glucocorticoids. FH-I is caused by a chimeric gene duplication between the homologous 11β-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) genes, fusing the adrenocorticotropic hormone (ACTH)–responsive 11β-hydroxylase promoter to the coding region of aldosterone synthase; this chimeric gene is under the control of ACTH and thus repressible by glucocorticoids. FH-III is caused by mutations in the KCNJ5 gene, which encodes the G-protein-activated inward rectifier K+ channel 4 (GIRK4); these mutations lead to the acquisition of sodium permeability in the mutant GIRK4 channels, causing an exaggerated membrane depolarization in adrenal glomerulosa cells and the activation of voltage-gated calcium channels. The resulting calcium influx is sufficient to produce aldosterone secretion and cell proliferation, leading to adrenal adenomas and hyperaldosteronism. Acquired causes of primary hyperaldosteronism include aldosterone-producing adenomas (APAs), primary or unilateral adrenal hyperplasia (PAH), idiopathic hyperaldosteronism (IHA) due to bilateral adrenal hyperplasia, and adrenal carcinoma; APA and IHA account for close to 60% and 40%, respectively, of diagnosed hyperaldosteronism. Acquired somatic mutations in KCNJ5 or less frequently in the ATP1A1 (an Na+/K+ ATPase α subunit) and ATP2B3 (a Ca2+ ATPase) genes can be detected in APAs; as in FH-III (see above), the exaggerated depolarization of adrenal glomerulosa cells caused by these mutations is implicated in the excessive adrenal proliferation and the exaggerated release of aldosterone. Random testing of plasma renin activity (PRA) and aldosterone is a helpful screening tool in hypokalemic and/or hypertensive patients, with an aldosterone:PRA ratio of >50 suggestive of primary hyperaldosteronism. Hypokalemia and multiple antihypertensive drugs may alter the aldosterone:PRA ratio by suppressing aldosterone or increasing PRA, leading to a ratio of <50 in patients who do in fact have primary hyperaldosteronism; therefore, the clinical context should always be considered when interpreting these results. The glucocorticoid cortisol has equal affinity for the mineralocorticoid receptor (MLR) to that of aldosterone, with resultant “mineralocorticoid-like” activity. However, cells in the aldosterone-sensitive distal nephron are protected from this “illicit” activation by the enzyme 11β-hydroxysteroid dehydrogenase-2 (11βHSD-2), which converts cortisol to cortisone; cortisone has minimal affinity for the MLR. Recessive loss-of-function mutations in the 11βHSD-2 gene are thus associated with cortisol-dependent activation of the MLR and the syndrome of apparent mineralocorticoid excess (SAME), encompassing hypertension, hypokalemia, hypercalciuria, and metabolic alkalosis, with suppressed PRA and suppressed aldosterone. A similar syndrome is caused by biochemical inhibition of 11βHSD-2 by glycyrrhetinic/glycyrrhizinic acid and/or carbenoxolone. Glycyrrhizinic acid is a natural sweetener found in licorice root, typically encountered in licorice and its many guises or as a flavoring agent in tobacco and food products. Finally, hypokalemia may also occur with systemic increases in glucocorticoids. In Cushing’s syndrome caused by increases in pituitary ACTH (Chap. 406), the incidence of hypokalemia is only 10%, whereas it is 60–100% in patients with ectopic secretion of ACTH, despite a similar incidence of hypertension. Indirect evidence suggests that the activity of renal 11βHSD-2 is reduced in patients with ectopic ACTH compared with Cushing’s syndrome, resulting in SAME. Finally, defects in multiple renal tubular transport pathways are associated with hypokalemia. For example, loss-of-function mutations in subunits of the acidifying H+-ATPase in alpha-intercalated cells cause hypokalemic distal renal tubular acidosis, as do many acquired disorders of the distal nephron. Liddle’s syndrome is caused by autosomal dominant gain-in-function mutations of ENaC subunits. Disease-associated mutations either activate the channel directly or abrogate aldosterone-inhibited retrieval of ENaC subunits from the plasma membrane; the end result is increased expression of activated ENaC channels at the plasma membrane of principal cells. Patients with Liddle’s syndrome classically manifest severe hypertension with hypokalemia, unresponsive to spironolactone yet sensitive to amiloride. Hypertension and hypokalemia are, however, variable aspects of the Liddle’s phenotype; more consistent features include a blunted aldosterone response to ACTH and reduced urinary aldosterone excretion. Loss of the transport functions of the TALH and DCT nephron segments causes hereditary hypokalemic alkalosis, Bartter’s syndrome (BS) and Gitelman’s syndrome (GS), respectively. Patients with classic BS typically suffer from polyuria and polydipsia, due to the reduction in renal concentrating ability. They may have an increase in urinary calcium excretion, and 20% are hypomagnesemic. Other features include marked activation of the renin-angiotensin-aldosterone axis. Patients with antenatal BS suffer from a severe systemic disorder characterized by marked electrolyte wasting, polyhydramnios, and hypercalciuria with nephrocalcinosis; renal prostaglandin synthesis and excretion are significantly increased, accounting for much of the systemic symptoms. There are five disease genes for BS, all of them functioning in some aspect of regulated Na+, K+, and Cl– transport by the TALH. In contrast, GS is genetically homogeneous, caused almost exclusively by loss-of-function mutations in the thiazide-sensitive Na+-Cl– cotransporter of the DCT. Patients with GS are uniformly hypomagnesemic and exhibit marked hypocalciuria, rather than the hypercalciuria typically seen in BS; urinary calcium excretion is thus a critical diagnostic test in GS. GS is a milder phenotype than BS; however, patients with GS may suffer from chondrocalcinosis, an abnormal deposition of calcium pyrophosphate dihydrate (CPPD) in joint cartilage (Chap. 339). Magnesium Deficiency and HypokalemiaMagnesium depletion has inhibitory effects on muscle Na+/K+-ATPase activity, reducing influx into muscle cells and causing a secondary kaliuresis. In addition, magnesium depletion causes exaggerated K+ secretion by the distal nephron; this effect is attributed to a reduction in the magnesium-dependent, intracellular block of K+ efflux through the secretory K+ channel of principal cells (ROMK; Fig. 63-4). In consequence, hypomagnesemic patients are clinically refractory to K+ replacement in the absence of Mg2+ repletion. Notably, magnesium deficiency is also a common concomitant of hypokalemia because many disorders of the distal nephron may cause both potassium and magnesium wasting (Chap. 339). Clinical FeaturesHypokalemia has prominent effects on cardiac, skeletal, and intestinal muscle cells. In particular, hypokalemia is a major risk factor for both ventricular and atrial arrhythmias. Hypokalemia predisposes to digoxin toxicity by a number of mechanisms, including reduced competition between K+ and digoxin for shared binding sites on cardiac Na+/K+-ATPase subunits. Electrocardiographic changes in hypokalemia include broad flat T waves, ST depression, and QT prolongation; these are most marked when serum K+ is <2.7 mmol/L. Hypokalemia can thus be an important precipitant of arrhythmia in patients with additional genetic or acquired causes of QT prolongation. Hypokalemia also results in hyperpolarization of skeletal muscle, thus impairing the capacity to depolarize and contract; weakness and even paralysis may ensue. It also causes a skeletal myopathy and predisposes to rhabdomyolysis. Finally, the paralytic effects of hypokalemia on intestinal smooth muscle may cause intestinal ileus. The functional effects of hypokalemia on the kidney can include Na+-Cl– and HCO3– retention, polyuria, phosphaturia, hypocitraturia, and an activation of renal ammoniagenesis. Bicarbonate retention and other acid-base effects of hypokalemia can contribute to the generation of metabolic alkalosis. Hypokalemic polyuria is due to a combination of central polydipsia and an AVP-resistant renal concentrating defect. Structural changes in the kidney due to hypokalemia include a relatively specific vacuolizing injury to proximal tubular cells, interstitial nephritis, and renal cysts. Hypokalemia also predisposes to acute kidney injury and can lead to end-stage renal disease in patients with long-standing hypokalemia due to eating disorders and/or laxative abuse. Hypokalemia and/or reduced dietary K+ are implicated in the pathophysiology and progression of hypertension, heart failure, and stroke. For example, short-term K+ restriction in healthy humans and patients with essential hypertension induces Na+-Cl– retention and hypertension. Correction of hypokalemia is particularly important in hypertensive patients treated with diuretics, in whom blood pressure improves with the establishment of normokalemia. Diagnostic ApproachThe cause of hypokalemia is usually evident from history, physical examination, and/or basic laboratory tests. The history should focus on medications (e.g., laxatives, diuretics, antibiotics), diet and dietary habits (e.g., licorice), and/or symptoms that suggest a particular cause (e.g., periodic weakness, diarrhea). The physical examination should pay particular attention to blood pressure, volume status, and signs suggestive of specific hypokalemic disorders, e.g., hyperthyroidism and Cushing’s syndrome. Initial laboratory evaluation should include electrolytes, BUN, creatinine, serum osmolality, Mg2+, Ca2+, a complete blood count, and urinary pH, osmolality, creatinine, and electrolytes (Fig. 63-7). The presence of a non–anion gap acidosis suggests a distal, hypokalemic renal tubular acidosis or diarrhea; calculation of the urinary anion gap can help differentiate these two diagnoses. Renal K+ excretion can be assessed with a 24-h urine collection; a 24-h K+ excretion of <15 mmol is indicative of an extrarenal cause of hypokalemia (Fig. 63-7). If only a random, spot urine sample is available, serum and urine osmolality can be used to calculate the transtubular K+ gradient (TTKG), which should be <3 in the presence of hypokalemia (see also “Hyperkalemia”). Alternatively, a urinary K+-to-creatinine ratio of >13 mmol/g creatinine (>1.5 mmol/mmol creatinine) is compatible with excessive renal K+ excretion. Urine Cl– is usually decreased in patients with hypokalemia from a nonreabsorbable anion, such as antibiotics or HCO3–. The most common causes of chronic hypokalemic alkalosis are surreptitious vomiting, diuretic abuse, and GS; these can be distinguished by the pattern of urinary electrolytes. Hypokalemic patients with vomiting due to bulimia will thus have a urinary Cl– <10 mmol/L; urine Na+, K+, and Cl– are persistently elevated in GS, due to loss of function in the thiazide-sensitive Na+-Cl– cotransporter, but less elevated in diuretic abuse and with greater variability. Urine diuretic screens for loop diuretics and thiazides may be necessary to further exclude diuretic abuse. FIGURE 63-7 The diagnostic approach to hypokalemia. See text for details. AME, apparent mineralocorticoid excess; BP, blood pressure; CCD, cortical collecting duct; DKA, diabetic ketoacidosis; FH-I, familial hyperaldosteronism type I; FHPP, familial hypokalemic periodic paralysis; GI, gastrointestinal; GRA, glucocorticoid remediable aldosteronism; HTN, hypertension; PA, primary aldosteronism; RAS, renal artery stenosis; RST, renin-secreting tumor; RTA, renal tubular acidosis; SAME, syndrome of apparent mineralocorticoid excess; TTKG, transtubular potassium gradient. (Used with permission from DB Mount, K Zandi-Nejad K: Disorders of potassium balance, in Brenner and Rector’s The Kidney, 8th ed, BM Brenner [ed]. Philadelphia, W.B. Saunders & Company, 2008, pp 547-587.)
Other tests, such as urinary Ca2+, thyroid function tests, and/or PRA and aldosterone levels, may also be appropriate in specific cases. A plasma aldosterone:PRA ratio of >50, due to suppression of circulating renin and an elevation of circulating aldosterone, is suggestive of hyperaldosteronism. Patients with hyperaldosteronism or apparent mineralocorticoid excess may require further testing, for example adrenal vein sampling (Chap. 406) or the clinically available testing for specific genetic causes (e.g., FH-I, SAME, Liddle’s syndrome). Patients with primary aldosteronism should thus be tested for the chimeric FH-I/GRA gene (see above) if they are younger than 20 years of age or have a family history of primary aldosteronism or stroke at a young age (<40 years). Preliminary differentiation of Liddle’s syndrome due to mutant ENaC channels from SAME due to mutant 11βHSD-2 (see above), both of which cause hypokalemia and hypertension with aldosterone suppression, can be made on a clinical basis and then confirmed by genetic analysis; patients with Liddle’s syndrome should respond to amiloride (ENaC inhibition) but not spironolactone, whereas patients with SAME will respond to spironolactone. TREATMENTTREATMENT Hypokalemia The goals of therapy in hypokalemia are to prevent life-threatening and/or serious chronic consequences, to replace the associated K+ deficit, and to correct the underlying cause and/or mitigate future hypokalemia. The urgency of therapy depends on the severity of hypokalemia, associated clinical factors (e.g., cardiac disease, digoxin therapy), and the rate of decline in serum K+. Patients with a prolonged QT interval and/or other risk factors for arrhythmia should be monitored by continuous cardiac telemetry during repletion. Urgent but cautious K+ replacement should be considered in patients with severe redistributive hypokalemia (plasma K+ concentration <2.5 mM) and/or when serious complications ensue; however, this approach has a risk of rebound hyperkalemia following acute resolution of the underlying cause. When excessive activity of the sympathetic nervous system is thought to play a dominant role in redistributive hypokalemia, as in TPP, theophylline overdose, and acute head injury, high-dose propranolol (3 mg/kg) should be considered; this nonspecific b-adrenergic blocker will correct hypokalemia without the risk of rebound hyperkalemia. Oral replacement with K+-Cl– is the mainstay of therapy in hypokalemia. Potassium phosphate, oral or IV, may be appropriate in patients with combined hypokalemia and hypophosphatemia. Potassium bicarbonate or potassium citrate should be considered in patients with concomitant metabolic acidosis. Notably, hypomagnesemic patients are refractory to K+ replacement alone, such that concomitant Mg2+ deficiency should always be corrected with oral or intravenous repletion. The deficit of K+ and the rate of correction should be estimated as accurately as possible; renal function, medications, and comorbid conditions such as diabetes should also be considered, so as to gauge the risk of overcorrection. In the absence of abnormal K+ redistribution, the total deficit correlates with serum K+, such that serum K+ drops by approximately 0.27 mM for every 100-mmol reduction in total-body stores; loss of 400–800 mmol of total-body K+ results in a reduction in serum K+ by approximately 2.0 mM. Notably, given the delay in redistributing potassium into intracellular compartments, this deficit must be replaced gradually over 24-48 h, with frequent monitoring of plasma K+ concentration to avoid transient overrepletion and transient hyperkalemia. The use of intravenous administration should be limited to patients unable to use the enteral route or in the setting of severe complications (e.g., paralysis, arrhythmia). Intravenous K+-Cl– should always be administered in saline solutions, rather than dextrose, because the dextrose-induced increase in insulin can acutely exacerbate hypokalemia. The peripheral intravenous dose is usually 20–40 mmol of K+-Cl– per liter; higher concentrations can cause localized pain from chemical phlebitis, irritation, and sclerosis. If hypokalemia is severe (<2.5 mmol/L) and/or critically symptomatic, intravenous K+-Cl– can be administered through a central vein with cardiac monitoring in an intensive care setting, at rates of 10–20 mmol/h; higher rates should be reserved for acutely life-threatening complications. The absolute amount of administered K+ should be restricted (e.g., 20 mmol in 100 mL of saline solution) to prevent inadvertent infusion of a large dose. Femoral veins are preferable, because infusion through internal jugular or subclavian central lines can acutely increase the local concentration of K+ and affect cardiac conduction. Strategies to minimize K+ losses should also be considered. These measures may include minimizing the dose of non-K+-sparing diuretics, restricting Na+ intake, and using clinically appropriate combinations of non-K+-sparing and K+-sparing medications (e.g., loop diuretics with angiotensin-converting enzyme inhibitors). HYPERKALEMIAHyperkalemia is defined as a plasma potassium level of 5.5 mM, occurring in up to 10% of hospitalized patients; severe hyperkalemia (>6.0 mM) occurs in approximately 1%, with a significantly increased risk of mortality. Although redistribution and reduced tissue uptake can acutely cause hyperkalemia, a decrease in renal K+ excretion is the most frequent underlying cause (Table 63-5). Excessive intake of K+ is a rare cause, given the adaptive capacity to increase renal secretion; however, dietary intake can have a major effect in susceptible patients, e.g., diabetics with hyporeninemic hypoaldosteronism and chronic kidney disease. Drugs that impact on the renin-angiotensin-aldosterone axis are also a major cause of hyperkalemia. TABLE 63-5Causes of Hyperkalemia View Table||Download (.pdf) TABLE 63-5Causes of Hyperkalemia
PseudohyperkalemiaHyperkalemia should be distinguished from factitious hyperkalemia or “pseudohyperkalemia,” an artifactual increase in serum K+ due to the release of K+ during or after venipuncture. Pseudohyperkalemia can occur in the setting of excessive muscle activity during venipuncture (e.g., fist clenching), a marked increase in cellular elements (thrombocytosis, leukocytosis, and/or erythrocytosis) with in vitro efflux of K+, and acute anxiety during venipuncture with respiratory alkalosis and redistributive hyperkalemia. Cooling of blood following venipuncture is another cause, due to reduced cellular uptake; the converse is the increased uptake of K+ by cells at high ambient temperatures, leading to normal values for hyperkalemic patients and/or to spurious hypokalemia in normokalemic patients. Finally, there are multiple genetic subtypes of hereditary pseudohyperkalemia, caused by increases in the passive K+ permeability of erythrocytes. For example, causative mutations have been described in the red cell anion exchanger (AE1, encoded by the SLC4A1 gene), leading to reduced red cell anion transport, hemolytic anemia, the acquisition of a novel AE1-mediated K+ leak, and pseudohyperkalemia. Redistribution and HyperkalemiaSeveral different mechanisms can induce an efflux of intracellular K+ and hyperkalemia. Acidemia is associated with cellular uptake of H+ and an associated efflux of K+; it is thought that this effective K+-H+ exchange serves to help maintain extracellular pH. Notably, this effect of acidosis is limited to non–anion gap causes of metabolic acidosis and, to a lesser extent, respiratory causes of acidosis; hyperkalemia due to an acidosis-induced shift of potassium from the cells into the ECF does not occur in the anion gap acidoses lactic acidosis and ketoacidosis. Hyperkalemia due to hypertonic mannitol, hypertonic saline, and intravenous immune globulin is generally attributed to a “solvent drag” effect, as water moves out of cells along the osmotic gradient. Diabetics are also prone to osmotic hyperkalemia in response to intravenous hypertonic glucose, when given without adequate insulin. Cationic amino acids, specifically lysine, arginine, and the structurally related drug epsilon-aminocaproic acid, cause efflux of K+ and hyperkalemia, through an effective cation-K+ exchange of unknown identity and mechanism. Digoxin inhibits Na+/K+-ATPase and impairs the uptake of K+ by skeletal muscle, such that digoxin overdose predictably results in hyperkalemia. Structurally related glycosides are found in specific plants (e.g., yellow oleander, foxglove) and in the cane toad, Bufo marinus (bufadienolide); ingestion of these substances and extracts thereof can also cause hyperkalemia. Finally, fluoride ions also inhibit Na+/K+-ATPase, such that fluoride poisoning is typically associated with hyperkalemia. Succinylcholine depolarizes muscle cells, causing an efflux of K+ through acetylcholine receptors (AChRs). The use of this agent is contraindicated in patients who have sustained thermal trauma, neuromuscular injury, disuse atrophy, mucositis, or prolonged immobilization. These disorders share a marked increase and redistribution of AChRs at the plasma membrane of muscle cells; depolarization of these upregulated AChRs by succinylcholine leads to an exaggerated efflux of K+ through the receptor-associated cation channels, resulting in acute hyperkalemia. Hyperkalemia Caused by Excess Intake or Tissue NecrosisIncreased intake of even small amounts of K+ may provoke severe hyperkalemia in patients with predisposing factors; hence, an assessment of dietary intake is crucial. Foods rich in potassium include tomatoes, bananas, and citrus fruits; occult sources of K+, particularly K+-containing salt substitutes, may also contribute significantly. Iatrogenic causes include simple overreplacement with K+-Cl– or the administration of a potassium-containing medication (e.g., K+-penicillin) to a susceptible patient. Red cell transfusion is a well-described cause of hyperkalemia, typically in the setting of massive transfusions. Finally, severe tissue necrosis, as in acute tumor lysis syndrome and rhabdomyolysis, will predictably cause hyperkalemia from the release of intracellular K+. Hypoaldosteronism and HyperkalemiaAldosterone release from the adrenal gland may be reduced by hyporeninemic hypoaldosteronism, medications, primary hypoaldosteronism, or isolated deficiency of ACTH (secondary hypoaldosteronism). Primary hypoaldosteronism may be genetic or acquired (Chap. 406) but is commonly caused by autoimmunity, either in Addison’s disease or in the context of a polyglandular endocrinopathy. HIV has surpassed tuberculosis as the most important infectious cause of adrenal insufficiency. The adrenal involvement in HIV disease is usually subclinical; however, adrenal insufficiency may be precipitated by stress, drugs such as ketoconazole that inhibit steroidogenesis, or the acute withdrawal of steroid agents such as megestrol. Hyporeninemic hypoaldosteronism is a very common predisposing factor in several overlapping subsets of hyperkalemic patients: diabetics, the elderly, and patients with renal insufficiency. Classically, patients should have suppressed PRA and aldosterone; approximately 50% have an associated acidosis, with a reduced renal excretion of NH4+, a positive urinary anion gap, and urine pH <5.5. Most patients are volume expanded, with secondary increases in circulating atrial natriuretic peptide (ANP) that inhibit both renal renin release and adrenal aldosterone release. Renal Disease and HyperkalemiaChronic kidney disease and end-stage kidney disease are very common causes of hyperkalemia, due to the associated deficit or absence of functioning nephrons. Hyperkalemia is more common in oliguric acute kidney injury; distal tubular flow rate and Na+ delivery are less limiting factors in nonoliguric patients. Hyperkalemia out of proportion to GFR can also be seen in the context of tubulointerstitial disease that affects the distal nephron, such as amyloidosis, sickle cell anemia, interstitial nephritis, and obstructive uropathy. Hereditary renal causes of hyperkalemia have overlapping clinical features with hypoaldosteronism, hence the diagnostic label pseudohypoaldosteronism (PHA). PHA type I (PHA-I) has both an autosomal recessive and an autosomal dominant form. The autosomal dominant form is due to loss-of-function mutations in the MLR; the recessive form is caused by various combinations of mutations in the three subunits of ENaC, resulting in impaired Na+ channel activity in principal cells and other tissues. Patients with recessive PHA-I suffer from lifelong salt wasting, hypotension, and hyperkalemia, whereas the phenotype of autosomal dominant PHA-I due to MLR dysfunction improves in adulthood. PHA type II (PHA-II; also known as hereditary hypertension with hyperkalemia) is in every respect the mirror image of GS caused by loss of function in NCC, the thiazide-sensitive Na+-Cl– cotransporter (see above); the clinical phenotype includes hypertension, hyperkalemia, hyperchloremic metabolic acidosis, suppressed PRA and aldosterone, hypercalciuria, and reduced bone density. PHA-II thus behaves like a gain of function in NCC, and treatment with thiazides results in resolution of the entire clinical phenotype. However, the NCC gene is not directly involved in PHA-II, which is caused by mutations in the WNK1 and WNK4 serine-threonine kinases or the upstream Kelch-like 3 (KLHL3) and Cullin 3 (CUL3), two components of an E3 ubiquitin ligase complex that regulates these kinases; these proteins collectively regulate NCC activity, with PHA-II-associated activation of the transporter.
Medication-Associated HyperkalemiaMost medications associated with hyperkalemia cause inhibition of some component of the renin-angiotensin-aldosterone axis. ACE inhibitors, angiotensin receptor blockers, renin inhibitors, and MLRs are predictable and common causes of hyperkalemia, particularly when prescribed in combination. The oral contraceptive agent Yasmin-28 contains the progestin drospirenone, which inhibits the MLR and can cause hyperkalemia in susceptible patients. Cyclosporine, tacrolimus, NSAIDs, and cyclooxygenase 2 (COX2) inhibitors cause hyperkalemia by multiple mechanisms, but share the ability to cause hyporeninemic hypoaldosteronism. Notably, most drugs that affect the renin-angiotensin-aldosterone axis also block the local adrenal response to hyperkalemia, thus attenuating the direct stimulation of aldosterone release by increased plasma K+ concentration. Inhibition of apical ENaC activity in the distal nephron by amiloride and other K+-sparing diuretics results in hyperkalemia, often with a voltage-dependent hyperchloremic acidosis and/or hypovolemic hyponatremia. Amiloride is structurally similar to the antibiotics trimethoprim (TMP) and pentamidine, which also block ENaC; risk factors for TMP-associated hyperkalemia include the administered dose, renal insufficiency, and hyporeninemic hypoaldosteronism. Indirect inhibition of ENaC at the plasma membrane is also a cause of drug-associated hyperkalemia; nafamostat, a protease inhibitor used in some countries for the management of pancreatitis, inhibits aldosterone-induced renal proteases that activate ENaC by proteolytic cleavage. Clinical FeaturesHyperkalemia is a medical emergency due to its effects on the heart. Cardiac arrhythmias associated with hyperkalemia include sinus bradycardia, sinus arrest, slow idioventricular rhythms, ventricular tachycardia, ventricular fibrillation, and asystole. Mild increases in extracellular K+ affect the repolarization phase of the cardiac action potential, resulting in changes in T-wave morphology; further increase in plasma K+ concentration depresses intracardiac conduction, with progressive prolongation of the PR and QRS intervals. Severe hyperkalemia results in loss of the P wave and a progressive widening of the QRS complex; development of a sine-wave sinoventricular rhythm suggests impending ventricular fibrillation or asystole. Hyperkalemia can also cause a type I Brugada pattern in the electrocardiogram (ECG), with a pseudo–right bundle branch block and persistent coved ST segment elevation in at least two precordial leads. This hyperkalemic Brugada’s sign occurs in critically ill patients with severe hyperkalemia and can be differentiated from genetic Brugada’s syndrome by an absence of P waves, marked QRS widening, and an abnormal QRS axis. Classically, the electrocardiographic manifestations in hyperkalemia progress from tall peaked T waves (5.5–6.5 mM), to a loss of P waves (6.5–7.5 mM) to a widened QRS complex (7.0–8.0 mM), and, ultimately, a to a sine wave pattern (>8.0 mM). However, these changes are notoriously insensitive, particularly in patients with chronic kidney disease or end-stage renal disease. Hyperkalemia from a variety of causes can also present with ascending paralysis, denoted secondary hyperkalemic paralysis to differentiate it from familial hyperkalemic periodic paralysis (HYPP). The presentation may include diaphragmatic paralysis and respiratory failure. Patients with familial HYPP develop myopathic weakness during hyperkalemia induced by increased K+ intake or rest after heavy exercise. Depolarization of skeletal muscle by hyperkalemia unmasks an inactivation defect in skeletal Na+ channel; autosomal dominant mutations in the SCN4A gene encoding this channel are the predominant cause. Within the kidney, hyperkalemia has negative effects on the ability to excrete an acid load, such that hyperkalemia per se can contribute to metabolic acidosis. This defect appears to be due in part to competition between K+ and NH4+ for reabsorption by the TALH and subsequent countercurrent multiplication, ultimately reducing the medullary gradient for NH3/NH4 excretion by the distal nephron. Regardless of the underlying mechanism, restoration of normokalemia can, in many instances, correct hyperkalemic metabolic acidosis. Diagnostic ApproachThe first priority in the management of hyperkalemia is to assess the need for emergency treatment, followed by a comprehensive workup to determine the cause (Fig. 63-8). History and physical examination should focus on medications, diet and dietary supplements, risk factors for kidney failure, reduction in urine output, blood pressure, and volume status. Initial laboratory tests should include electrolytes, BUN, creatinine, serum osmolality, Mg2+ and Ca2+, a complete blood count, and urinary pH, osmolality, creatinine, and electrolytes. A urine Na+ concentration of <20 mM indicates that distal Na+ delivery is a limiting factor in K+ excretion; volume repletion with 0.9% saline or treatment with furosemide may be effective in reducing plasma K+ concentration. Serum and urine osmolality are required for calculation of the transtubular K+ gradient (TTKG) (Fig. 63-8). The expected values of the TTKG are largely based on historical data, and are <3 in the presence of hypokalemia and >7–8 in the presence of hyperkalemia.
FIGURE 63-8 The diagnostic approach to hyperkalemia. See text for details. ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CCD, cortical collecting duct; ECG, electrocardiogram; ECV, effective circulatory volume; GFR, glomerular filtration rate; GN, glomerulonephritis; HIV, human immunodeficiency virus; LMW heparin, low-molecular-weight heparin; NSAIDs, nonsteroidal anti-inflammatory drugs; PHA, pseudohypoaldosteronism; SLE, systemic lupus erythematosus; TTKG, transtubular potassium gradient. (Used with permission from DB Mount, K Zandi-Nejad K: Disorders of potassium balance, in Brenner and Rector’s The Kidney, 8th ed, BM Brenner [ed]. Philadelphia, W.B. Saunders & Company, 2008, pp 547-587.)
TREATMENTTREATMENT Hyperkalemia Electrocardiographic manifestations of hyperkalemia should be considered a medical emergency and treated urgently. However, patients with significant hyperkalemia (plasma K+ concentration ≥6.5 mM) in the absence of ECG changes should also be aggressively managed, given the limitations of ECG changes as a predictor of cardiac toxicity. Urgent management of hyperkalemia includes admission to the hospital, continuous cardiac monitoring, and immediate treatment. The treatment of hyperkalemia is divided into three stages:
Therapy with intravenous saline may be beneficial in hypovolemic patients with oliguria and decreased distal delivery of Na+, with the associated reductions in renal K+ excretion. Loop and thiazide diuretics can be used to reduce plasma K+ concentration in volume-replete or hypervolemic patients with sufficient renal function for a diuretic response; this may need to be combined with intravenous saline or isotonic bicarbonate to achieve or maintain euvolemia. Hemodialysis is the most effective and reliable method to reduce plasma K+ concentration; peritoneal dialysis is considerably less effective. Patients with acute kidney injury require temporary, urgent venous access for hemodialysis, with the attendant risks; in contrast, patients with ESRD or advanced chronic kidney disease may have a preexisting venous access. The amount of K+ removed during hemodialysis depends on the relative distribution of K+ between ICF and ECF (potentially affected by prior therapy for hyperkalemia), the type and surface area of the dialyzer used, dialysate and blood flow rates, dialysate flow rate, dialysis duration, and the plasma-to-dialysate K+ gradient. What are some risk factors for developing electrolyte imbalances?What are the risk factors for an electrolyte imbalance?. Burns.. Cancer.. Cardiovascular disease, heart failure or high blood pressure.. Dehydration due to not drinking enough liquids or from excessive vomiting, diarrhea, sweating (hyperhidrosis) or fever.. Overhydration or water intoxication (drinking too much water).. What are 4 signs of an electrolyte imbalance?When the amount of electrolytes in your body is too high or too low, you can develop:. Dizziness.. Cramps.. Irregular heartbeat.. Mental confusion.. Which groups are at risk for fluid imbalance?Risk factors for electrolyte imbalances. adrenal gland disorders.. alcoholism and cirrhosis.. congestive heart failure.. cancer treatment.. kidney disease.. eating disorders.. physical trauma (burns or broken bones). thyroid disorders.. What causes electrolyte imbalance in elderly?Older adults may be more susceptible to dehydration and electrolyte imbalances than younger adults. There are many reasons for this, including the following: The kidneys may lose some of their function with age. Older adults may take multiple medications, such as diuretics, that can change electrolyte levels.
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Which factor-may increase the risk for developing john’s electrolyte imbalance?
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