Disorders of Sodium and Potassium Metabolism

Physiology:

Regulation of sodium and potassium balance is a complex process, predominantly occurring in the kidney, and involving a number of hormones and other mediators including the renin-angiotensin-aldosterone system. In addition, it is linked to free water balance and overall acid-base status.

Renin – A protease produced by the juxtaglomerular cells of the kidney in response to low renal perfusion pressure, with a minor stimulatory effect from increased sympathetic tone (from epinephrine and norepinephrine).

Angiotensin II – An octapeptide produced from angiontensin I in the lungs and kidneys. Actions:1. Stimulates cells in the zona glomerulosa of the adrenal cortex to produce aldosterone.2. Acts directly on the arterioles to cause vasoconstriction.3. Stimulates Na+/H+ exchange in the renal proximal tubule, which also aids in the reabsorption of HCO3

-.

Aldosterone – A steroid hormone that acts in the late distal tubule and collecting duct. Actions:1. Stimulates the reabsorption of NaCl and the secretion of potassium by the principal cells.2. Increases the activity of the H+ ATPase secretory pumps in the intercalated cells.

ADH (antidiuretic hormone, aka arginine vasopressin) – A polypeptide synthesized in the hypothalamus and stored in the posterior pituitary, where they are released in response to plasma hyperosmolality and decreased effective circulating volume. There is no significant change in ADH levels in mild volume depletion, but in severe volume depletion and hypotension ADH levels can far exceed those induced by hyperosmolality. Actions:

1. Increases collecting tubule water permeability by inducing the activation of preformed water channels, leading to a concentration of the urine. (Mediated by ADH V2 receptors)

2. Mildly increases vascular resistance (Mediated by ADH V1 receptors)

ANP (atrial natriuretic peptide) – A polypeptide secreted by myocardial cells in the atria (right>left) in response to atrial stretch, as is seen in hypervolemia. Although it has a large number of actions, physiologically it acts as only a weak natriuretic agent. Actions:

1. Blocks sodium reabsorption in the medullary collecting tubules.2. Acts as a direct vasodilator, decreasing systemic blood pressure.3. Increases GFR, possibly through the combination of afferent arteriolar dilation and efferent arteriolar constriction.4. Inhibits the renin-anigotensin-aldosterone system at a variety of points.

BNP (brain natriuertic peptide) – A polypeptide secreted by the brain and by myocardium (ventricles>atria) in response to cardiac failure. Its actions are similar to those of ANP.

Plasma Osmolality vs. Tonicity – The plasma osmolality (Posm) is determined solely by the ratio of overall plasma solutes and plasma water. Plasma tonicity is determined by only those solutes that determine the transcellular movement of water. For example, since urea is an ineffective osmole, urea accumulation in renal failure does not lead to movement of water across the cell membrane. Despite their name, osmoreceptors (such as those responsible for ADH secretion) actually sense plasma tonicity.

Hypovolemia vs. Dehydration – Dehydration refers to pure water loss and an intracellular water deficit due to the osmotic movement of water from the cells into the extracellular fluid. Hypovolemia refers to the combination of salt and water loss (as seen in vomiting, diarrhea, bleeding, etc…). Dehydrated patients are always hypernatremic, whereas hypovolemic patients are typically normonatremic or hyponatremic. As hypovolemia comes predominantly at the expense of the extracellular fluid, whereas dehydration comes at the expense of total body water, for dehydration to produce the same degree of extracellular volume depletion as salt and water loss, about 2.5 times as much fluid would have to be lost.

Overview of Regulation of Renal Sodium Balance – Renal Na+ excretion varies directly with the effective circulating volume (ECV). In general, it is changes in tubular reabsorption (rather than changes in GFR) that constitute the main adaptive response to changes in ECV. Although the loop of Henle and distal tubule are important overall segments in Na+ reabsorption, reabsorption here is largely flow dependent. The more significant neurohumoral regulation of sodium balance occurs in the proximal and collecting tubules. Despite the probable importance of aldosterone in sodium excretion, abnormalities in its secretion rarely are associated with derangements in sodium balance because other factors are able to compensate.

Overview of the handling of electrolytes by the nephron:

Hyponatremia

Symptoms:

Symptoms from a derangement of sodium are not just related to the severity of the derangement, but also to the speed of its development. They are generally neurologic in nature, and include headaches, nausea/vomiting, mental status changes, seizures, and coma. In hyponatremia, the exact mechanism leading to these symptoms is thought to be cerebral edema created by the osmolal gradient which favors water movement into cells during states of hypotonicity. The degree of cerebral edema is much less when the onset of hyponatremia is gradual (>3 days), partially due to the transport of organic solutes (known as osmolytes) out of neurons and into the extracellular space, minimizing fluid shift into the cells. For unclear reasons, premenopausal women are less able to undertake this adaptive response.

Signs / ECG Abnormalities: There are no specific signs or ECG changes seen in hyponatremia.

Etiologies:

Primary Sodium LossPoor Intake of Sodium

Excessive beer consumption (known as beer drinker’s potomania)“Tea and toast diet” (a condition, most often described in malnourished elderly, in which a patient manages to

drink adequate fluids, despite an otherwise poor diet).Increased Urinary Excretion (See sections on hypokalemia and hyperkalemia for more information on these conditions,

as most have a greater effect on potassium balance)Decreased sodium uptake in the proximal tubule

Proximal (type 2) RTACarbonic anhydrase inhibitors (e.g. acetazolamide)

Decreased sodium uptake in the thick ascending limb of the loop of HenleLoop diuretics (e.g. furosemide)Bartter’s syndrome

Decreased sodium uptake in the early distal tubuleThiazide diuretics (e.g. hydrochlorothiazide)Gitelman’s syndrome

Decreased sodium uptake in the late distal tubuleAldosterone deficiency Aldosterone resistance

Fluid loss followed by repletion with hyponatremic solutions (for example, excessive sweating in marathon runners, followed by repletion with free water)

Primary Water ExcessExcessive intake (aka primary polydipsia. A daily H2O consumption > 15L is needed to develop hyponatremia)

PsychosisEcstasyHypothalamic lesions (such as those that occur due to infiltrative disease like sarcoidosis)

Decreased water excretionDecreased GFR (Generally seen only with advanced renal failure, as opposed to early renal failure)Increased ADH

Decreased effective circulating volumeTrue volume depletion

VomitingDiarrheaBlood lossIncreased insensible losses

Apparent volume depletion (with subsequent development of hypervolemia)Heart failureCirrhosis Nephrotic syndrome

Reset osmostat (condition in which ADH levels are appropriately suppressed by hypotonicity, but at a lower plasma osmolality than normal. This occurs predominantly in states of severe debilitation, such as malnutrition, metastatic cancer, and advanced tuberculosis. Reset osmostat is occasionally considered a form of SIADH)

SIADHMalignancy

Small cell carcinoma of the lungOther lung cancersPancreatic cancerOlfactory neuroblastoma

CNS pathology (nearly any type of CNS pathology has been associated with SIADH)Pulmonary pathology

PneumoniaAsthma/COPDPneumothorax

DrugsCarbamazepineIV CyclophosphamideHaloperidolSSRIs (e.g. fluoxetine, sertraline)Vincristine/vinblastin/cisplatinAmitriptylineEcstasy

Exogenous hormonesVasopressinOxytocinDesmopressin (aka DDAVP)

EndocrinopathiesHypothyroidism (unclear mechanism)Adrenal insufficiency (due to cortisol deficiency)

Severe pain of any etiology (most typically following surgery)Transsphenoidal pituitary surgery (due to direct injury to the posterior pituitary)(It has been observed that acutely psychotic patients occasionally suffer from SIADH.

Whether this is because the psychosis directly leads to ADH release, or because the psychosis and SIADH are both manifestations of another undiagnosed primary abnormality is unclear.)

Cerebral salt-wasting (A rare syndrome has been described in patients with cerebral disease, particularly subarachnoid hemorrhage, that mimics SIADH).

Transcellular shift of water (secondary to hyperosmolality of the plasma)Hyperglycemia (for each 100mg/dL rise in glucose above 100mg/dL, [Na+] should fall by 1.6mEq/L)Administration of mannitol

Pseudohyponatremia (a collection of disorders in which marked elevations of substances result in a reduction in the fraction of plasma that is water and an artificially low sodium concentration)

Severe hyperlipidemiaHyperproteinemia

Diagnosis:

In diagnosing the etiology of hyponatremia, there are 4 major parameters that should be evaluated – overall volume status, plasma osmolality (Posm), urine osmolality (Uosm), and UNa.

Patients with reset osmostat can be distinguished from those with SIADH by their ability to appropriately dilute their urine after an acute oral water load (20ml/kg). In reset osmostat, the Uosm should drop below 100 mOsm/kg and >80% of this water should be excreted over the course of 4 hours. In SIADH, the Uosm will still be >100 mOsm/kg, and less than 60% of the water load will be excreted at 4 hours. Direct measurement of plasma vasopressin levels is not helpful in making a diagnosis of SIADH because an elevation in his hormone can be seen in all causes of hypotonic hyponatremia (with the exception of primary polydipsia).

Treatment:

Indications for hospitalization, aside from those for the underlying disorder, are neurologic symptoms or serum [Na+] < 125 mEq/L.

The rate of correction should not exceed 0.5 mEq/L/hr, unless patient is having severe neurologic symptoms, due to the risk of precipitating central pontine myelinosis (aka osmotic demyelination syndrome). This commonly fatal disorder consists of demyelination of loss of axons, predominantly in the pons, as the name implies. It manifests as spastic quadriplegia, pseudobulbar palsy, and varying degrees of encephalopathy or coma; in its complete form, patients develop the “locked-in syndrome”. It usually develops 48-72 hours after correction of hyponatremia. In addition to confusion and spastic quadriplegia, horizontal gaze paralysis is a clue to the diagnosis. Prognosis is poor, and the diagnosis itself is frequently made after death. Although most frequently associated with rapid correction of hyponatremia, it is also seen in hypernatremia, azotemia, and hyperglycemia, and is more common in alcoholics. In patients who survive, full recovery may take months.

Hypervolemic hyponatremia – Sodium restriction (1-3gm/day) and free water restriction (1-1.5 L/day)

Euvolemic hyponatremia – Free water restriction only

Hypovolemic hyponatremia – Replace water with 0.9% NaCl (normal saline)

Total body sodium deficit = 0.6 x IBW x (140 – measured [Na+]) x (0.85 in women)

Total # of L of NS needed to correct [Na+] = Na+ deficit / 154 mEq/L

Duration of correction (hrs) = (140 – measured [Na+]) / 0.5 mEq/L/hr

Rate of correction (L/hr) ≈ [IBW (in kg) / 500 ] x 0.85 in women

Severe hyponatremia accompanied by seizures or coma can be treated more rapidly with 3% NaCl.

Hypernatremia

Symptoms:

In hypernatremia, the rise in plasma sodium leads to water movement out of the brain, in which the decrease in brain volume can lead to rupture of the cerebral veins with focal subarachnoid and intracerebral hemorrhage. Symptoms are generally similar to those which occur in hyponatremia. Severe symptoms usually require an acute rise in serum sodium to above 158meq/L.

Signs / ECG Abnormalities: There are no specific signs or ECG changes seen in hyponatremia.

Etiologies:

Excess intake of sodium (usually rapidly corrects in the setting of normal renal function)Hypertonic saline solutions (e.g. 3% NaCl, NaHCO3)Accidental or nonaccidental salt poisoning in infants and young children

Increased renal reabsorption of sodium (rare cause of hypernatremia because the thirst mechanism which will generally act to normalize plasma sodium at the expense of mild hypervolemia)

Hyperaldosteronism

Decreased water intake/Increased water excretion (these two categories should be considered together, as any condition which results in increased water loss will only result in hypernatremia if there is concomitant impairment in either thirst or in access to free water, as serum hypertonicity is a very strong promoter of thirst).

Impaired access to waterInfantsElderly patients with dementia or who are bed-bound.

Impaired thirst sensation (aka hypodipsia. Almost always due to hypothalamic disease.)TumorGranulomatous disease (e.g. sarcoidosis)Vascular diseaseReset osmostat (aka essential hypernatremia – seen only in patients with primary mineralocorticoid excess)

Increased insensible lossesFeverExposure to high temperaturesExercise

GI losses (particularly in osmotic diarrheas)

Impaired reabsoprtion of water in the collecting duct (aka Diabetes Insipidus or DI)

ADH Deficiency (Central DI)Decreased Production and/or Impaired Release

Familial CDI (rare autosomal dominant disorder)Idiopathic (may be due to an autoimmune process in some patients and occult pituitary or

sellar process in others. 30-50% of cases of central DI are initially labeled idiopathic).Neurosurgery (seen most commonly in transsphenoidal surgery and seen in 10-20% of

cases involving the removal of small pituitary adenomas).TraumaTumorsEncephalitisSheehan’s syndrome (postpartum pituitary infarction)Infiltrative diseases

Langerhans cell histiocytosis SarcoidosisWegener’s granulomatosis

Hypoxic encephalopathyIncreased Degradation

Gestational DI (occurs during the second half of pregnancy due to the placenta secreting a vasopressinase, which leads to the rapid degradation of ADH)

ADH Resistance (Nephrogenic DI – due to resistance either at the ADH site of action in the collecting tubules, or due to interference with the countercurrent mechanism, which can be develop from medullary injury or from decreased sodium chloride reabsorption in the thick ascending limb of the loop of Henle.)

Lithium toxicity (occurs in up to 20% of patients on chronic lithium therapy, with an additional 30% having subclinical impairment in concentrating ability).

Hereditary NDI (A usually X-linked disorder). Hypercalcemia (can be seen if serum [Ca+2] > 11 mg/dL consistently). Hypokalemia (can be seen in serum [K+] < 3 meq/L consistently.)Neurosurgery (seen in patients after transfrontal surgery for craniopharyngioma).Sickle Cell DiseaseAmyloidosis (probably due to amyloid deposits in the collecting tubules)Sjogren’s disease (probably due to lymphocytic infiltration around the collecting tubules)Decreased GFR from any cause (partial nephrogenic DI is a relatively common finding in hospitalized

and elderly patients due to decreased GFR, however, the mild to moderate decline in urine concentrating ability is not usually sufficient to produce polyuria and/or hypernatremia, though may play a contributing role when another etiology of hypernatremia is also present.)

Primary Impairment in the counter-current mechanismOsmotic diuresis (from mannitol, glucose, or urea)

Internal redistribution of water (occurs due to hyperacute increase in intracellular osmolality, most often from the rapid breakdown of glycogen into lactate. The hypernatremia usually resolves within 5-15 minutes from cessation of activity)

Vigorous exercise Seizures

Diagnosis:

As noted elsewhere, all causes of hypernatremia must also be in the setting of either impaired access to free water or an impaired thirst mechanism due to hypothalamic disease, as plasma hyperosmolality is a powerful inducer of thirst.

Treatment:

The rate of correction should not exceed 0.5 mEq/L/hr, unless patient is having severe neurologic symptoms, due to the risk of precipitating cerebral edema, seizures, and death.

Free Water Deficit = Total Body Water x [(Plasma [Na+] / 140) – 1]Total Body Water (L) = 0.6 x IBW (kg) x (0.85 in women) x (0.9 if patient appears hypovolemic)Duration of correction (hrs) = [(Plasma [Na+]) – 140] / 0.5

Rate of Correction (L/hr) = (Free Water Deficit)/(Duration of Correction) 1 – (NaCl content of replacement fluid / 0.9%)

Using substitution, the rate of correction (mL/hr) = 2.1 x IBW x (0.85 in women) x (0.9 in hypovolemia) 1 – (NaCl content of replacement fluid / 0.9%)

(Note that only the duration of correction, and not the rate, is dependent upon the initial [Na+])

If patient is hypovolemic, one should use ½ NS or ¼ NS.If patient is hypervolemic, one should give D5W + IV furosemide

It is important to note, that while the patient is receiving corrective IV fluid replacement, he is continuing to experience free water loss (which also needs to be replaced) unless the initial etiologic cause has been identified and appropriately treated (such as treatment for an osmotic diarrhea).

Hypokalemia

Symptoms: Nausea/vomiting, weakness, muscle cramps

Symptoms generally do not occur unless plasma [K+] < 3.0, except in heart disease and cirrhosis, in which case symptoms can occur with more mild abnormalities.

ECG Abnormalities: Mild (3.0-3.5 mEq/L) – T waves lose amplitude

Moderate (2.5-3.0 mEq/L) – T waves become flattened, ST segments become depressed, and U waves become more prominent.Arrhythmias may develop especially if the patient is taking digitalis.

Severe (<2.5 mEq/L) – Risk of arrhythmias rises quickly. QRS prolongation may also occur but is uncommon.

Contrary to popular belief, the QT interval does not prolong in hypokalemia. This appearance is the result of the prominent U wave and TU fusion.

Etiologies:

Poor intake (Uncommon in isolation, but can often worsen hypokalemia due to another cause)Anorexia nervosa / Bulimia“Tea and toast” diet

Decreased GI AbsorptionDiarrheaVillous adenoma (rare)Ureterosigmoidostomy (probably due to urine ammonium ions competing with potassium for absorption)Laxative abuseVomiting / NG drainage (hypokalemia in these settings are largely due to metabolic alkalosis leading to excessive

sodium bicarbonate delivery to the distal tube, in addition to hypovolemia inducing aldosterone release).

Increased Urinary Excretion

Decreased reabsorption in the loop of HenleMedications

Loop diuretics (e.g. furosemide)Bartter’s syndrome (a rare autosomal recessive disorder which grossly mimics treatment with a loop diuretic).

Increased excretion in late distal tubuleIncreased delivery of sodium to the distal tubule

Proximal (type 2) RTAFanconi’s syndromeAmyloidosisMultiple myeloma

Thiazide diuretics (e.g. hydrochlorothiazide)Loop diuretics (e.g. furosemide)Gitelman’s syndrome (an uncommon autosomal recessive disorder caused by a defect in the Na-Cl

cotransporter in the early distal tubule. This, combined with the more serious Barrter’s syndrome, are rare etiologies of hypokalemia and metabolic alkalosis in a normotensive patient. Together, these are often referred to as salt-wasting nephropathies)

Carbonic anhydrase inhibitors (e.g. acetazolamide. Mimics proximal RTA)DKA (due to glucose osmotic diuresis. True potassium depletion is usually masked by transcelluar

shifts until correction of the acidosis)

Reduced function of K+/H+ ATPase in the late distal tubuleThe most common form of distal (type 1) RTA

Autoimmune (best described in Sjogren’s syndrome)Variety of hereditary defects

Increased permeability of the luminal membrane to potassiumAmphotericin B

Excess mineralocorticoidsElevated serum aldosterone

Primary hyperaldosteronismAldosterone-secreting adrenal adenoma (65% of cases of 1° hyperaldosteronism)Idiopathic adrenal hyperplasiaCongenital adrenal hyperplasia

17α hydroxylase deficiency11β hydroxylase deficiency

Adrenal carcinomaFamilial hyperaldosteronism

Secondary hyperaldosteronismRenovascular hypertension

Renal artery stenosisRenal artery atherosclerosisRenal artery vasculitis

Renin secreting tumorPseudohyperaldosteronism

Cushing’s syndrome (due to the mineralocorticoid actions of the excessive cortisol)Exogenous mineralocorticoids

Fludrocortisone acetate (aka Florinef)Intranasal corticosteroids

Exogenous 11β hydroxysteroid dehydrogenase inhibitorsGlycyrrhizic acid (present in licorice and some chewing tobacco)

Increased delivery of non-reabsorbable anions to the distal nephron (in this setting, more of the sodium delivered to the late distal tubule will be exchanged for potassium)

Vomiting/Type 2 RTA (due to bicarbonate)DKA (due to β hydroxybutyrate)

Severe chronic polyuria (due to excessive filtration of potassium overwhelming the reabsorption capacity of the nephron. This is seen most predominantly in psychogenic polydipsia.)

Transcutaneous losses from copious perspiration

Internal RedistributionAlkalosis (a relatively small effect, with a decrease in plasma [K+] of 0.4meq/L for every 0.1 unit rise in pH)Increased availability of insulin (seen most commonly during treatment for DKA or non-ketotic hyperglycemia coma)High catecholamine states (predominantly seen in severe acute illness, and coronary ischemia)Hypokalemic periodic paralysis (a rare disorder of uncertain cause characterized by potentially fatal episodes of muscle

weakness or paralysis which can affect the respiratory muscles)Marked increase in blood cell production

During treatment for megaloblastic anemia with folic acid or vitamin B12During treatment for neutropenia with GM-CSFAcute myeloid leukemia

Unknown MechanismHypomagnesemia

Diagnosis:

All patients with hypokalemia and hypertension should be screened with plasma aldosterone and renin levels for signs of primary or secondary hyperaldosteronism. An elevated plasma aldosterone to renin ratio is suggestive of primary hyperaldosteronism, which should be confirmed by an aldosterone suppression test.

Treatment:

As there is no strict correlation between plasma potassium concentration and total body potassium stores. In general, for every 1mEq/L that the plasma potassium is below 4.0, there is a total body deficit of 200-400meq. Repletion of potassium should always be accompanied by repletion of magnesium in hypomagnesemic states.

Mild to moderate hypokalemia ([K+] > 3.0): Treat the underlying disorder, if possible~ 60-80 mEq/day of PO KClK-sparing diuretics are more effective in hypokalemia

due to chronic diuretic use

Severe hypokalemia ([K+] < 3.0, or symptomatic):

IV KCl (10-20 mEq/hr. A maximum of 60mEq should be given via a single peripheral vein)

Simultaneous supplementation with PO KCl

Increasing intake of potassium-rich foods as chronic treatment of hypokalemia is less effective than potassium chloride supplementation, due to their generally high content of phosphate and citrate.

Hyperkalemia

Symptoms: Symptoms of hyperkalemia can be related to impaired neuromuscular transmission, the most prominent of which is muscle weakness. Severe symptoms usually do not occur until the plasma [K+] > 7.0 meq/L (unless the rise has been very rapid). Hypocalcemia and metabolic acidosis can increase the toxicity of excess potassium, and the risk of developing symptoms and cardiac arrhythmias.

ECG Abnormalities: Mild to Moderate (5.5-7.0 mEq/L) –

Tall, narrow, peaked T waves develop.

Marked (7.0-9.0 mEq/L) – P wave amplitude decreases, QRS widening and ST changes develop. Sinus arrest or varying degrees of AV block may occur.

Severe (>9.0 mEq/L) – QRS becomes “sinusoidal” in appearance; cardiac arrest (usually from ventricular fibrillation) quickly follows.

In marked and severe hyperkalemia, the atrial muscle may be paralyzed, with normal ventricular contraction. As the normal sinus impulses conducting to the AV junction without activating the atria, this situation may mimic a junctional rhythm.

Etiologies:

Increased Dietary Intake (does not lead to hyperkalemia unless very acute ingestion of >400meq KCl over 1 day, or in the setting of other causes of hyperkalemia, such as renal failure)

Increased GI absorptionUreterojejunostomy

Decreased Urinary Excretion (which is due solely to decreased excretion in the late distal tubule)Decreased number of functioning nephrons

Renal failure (does not occurs until GFR < 20mL/min, and will not occur as an isolated cause of hyperkalemia until GFR < 5mL/min)

Decreased delivery of sodium to the late distal tubuleDecreased effective circulating volume (due to stimulation of the conversion of prorenin to renin, leading to

increased circulating angiotensin II and increased reabsorption of sodium in the proximal tubule)Heart failureCirrhosis

Type 2 psuedohypoaldosteronism (aka Gordon’s syndrome, or familial hyperkalemic hypertension – a genetically heterogenous, but phenotypically homogenous, group of rare hereditary disorders associated with increased activity of the Na-Cl cotransporter in the early distal tubule).

Impairment of potassium excretion in the late distal tubule Aldosterone deficiency (aka hypoaldosteronism or type 4 RTA)

Primary aldosterone deficiencyPrimary adrenal insufficiency (aka Addison’s disease)Congenital adrenal hyperplasia

21-hydroxylase deficiencyHeparin and LMWH (due to a direct toxic effect on the adrenal zona glomerulosa cells)

Hyporeninemic hypoaldosteronismDiabetic nephropathy (due to impaired conversion of prorenin to renin)Acute glomerular nephritis

NSAIDs (due to the fact that renin secretion is normally mediated in part by locally produced prostaglandins, the production of which is inhibited by NSAIDs. This occurs predominantly in patients with renal insufficiency.)

HIV (unknown mechanism)Impaired conversion of angiotensin I to angiotensin II

ACE inhibitorsSevere illness (hypersecretion of ACTH in severe illness may diminish aldosterone production by

shunting precursors to the synthesis of cortisol)Aldosterone resistance (aldosterone levels may be normal or even high)

Blockage of the normal sodium channel in the principal cell (reabsorption of sodium in the late distal tubule and collecting duct is necessary to make the lumen electronegative, which promotes the movement of both K+ and H+ into the urine)

Potassium sparing diuretics (e.g. spironolactone, amiloride, triamterene)TrimethoprimPentamidine

Type 1 pseudohypoaldosteronism (heterogeneous group of rare hereditary disorders which usually present in infancy)

Autosomal recessive form (due to a defect is in the sodium channel in the collecting tubule - and other aldosterone target organs - making it relatively unresponsive to aldosterone)

Autosomal dominant form (due to mutations in the gene for the mineralocorticoid receptor. Patient with this form may clinically improve with age)

Selective impairment of potassium secretionAcute transplant rejectionLupus nephritisAmyloidosisSickle-cell diseaseObstructive uropathyCyclosporine (specific mechanism is not entirely clear, but this effect can be particularly pronounced when

cyclosporine is combined with an ACE inhibitor)

Internal RedistributionTranscellular shift

Acidosis ([K+] increases by 0.6mEq/L per 0.1 decrease in pH)Beta blockers (rare cause of clinically significant hyperkalemia in isolation, but can be a significant factor when

combined with another cause of hyperkalemia – such as extreme exercise in the setting of β blocker use)Exercise (typically associated with mild rebound hypokalemia occurring several minutes after rest)Digoxin toxicityUncontrolled IDDM (due to insulin deficiency)SuccinylcholineHyperkalemic periodic paralysis (an autosomal dominant disorder in which episodes of weakness or paralysis

are usually precipitated by cold exposure, rest after exercise, or the ingestion of small amounts of potassium.)

Cell lysisRhabdomyolysisTumor lysis syndromeIschemic bowel.

PseudohyperkalemiaCell lysis during/following phlebotomy (strongly suggested by the reddish tint of the serum due to the concomitant

release of hemoglobin)Mechanical trauma

Temperature-dependent leakage of potassium out of RBCsHereditary spherocytosisFamilial pseduohyperkalemia

Post-clot transcellular shift (potassium moves out of white blood cells and platelets after clot formation. This effect is minimal in patients with normal cell counts, but can be pronounced in extreme leukocytosis or thrombocytosis)

Diagnosis:

First, rule out pseudohyperkalemia, cell lysis and transcellular shifts. Then proceed with the following algorithm:

Treatment:

Drug Dosing Mechanism Time to Onset Duration of Effect

Calcium 10mL of 10% calcium gluconate, given over 2-3 minutes with constant cardiac monitoring

Antagonizes membrane actions of K+

<5 minutes 30-60 minutes

Insulin + Glucose

10 units regular insulin + 1 amp D50, followed by continuous glucose infusion

Drives K+ into cells

15 -30 minutes 4-6 hours

Albuterol 20mg in 4mL saline inhaled over 10 minutes

Drives K+ into cells

15-30 minutes 1 hour

Sodium Bicarbonate

50 meq IV, given over 5 minutes Drives K+ into cells

30 minutes 2 hours

Furosemide Varies, but can give 40mg IV Removes K+ from the body

30 minutes 4-6 hours

Kayexalate 20 grams given with 100mL of a 20% sorbitol solution PO or PR, q4-6hrs

Removes K+ from the body

60 minutes 4-6 hours

Dialysis - Removes K+ from the body

< 5 minutes -