ELECTROLYTES

• ACRONYMS AND DEFINITIONS

• ADH - Antidiuretic hormone, also called "arginine vasopressin" or just "vasopressin"
• CKD - Chronic kidney disease
• CrCl - Creatinine Clearance
• DDAVP - Desmopressin, synthetic ADH
• DI - Diabetes insipidus
• ECG - Electrocardiogram
• GFR - Glomerular filtration rate
• mEq - milliequivalent
• mmol - millimole
• mOsm - milliosmole
• NKF - National Kidney Foundation
• PI - Prescribing information or package insert
• PTH - Parathyroid hormone
• RAAS - Renin-angiotensin-aldosterone system
• SIADH - Syndrome of inappropriate ADH

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• Definitions

• Free water - free water is water without solutes. Along the nephron, water is mostly reabsorbed with sodium and chloride. In the distal collecting duct, ADH stimulates the formation of pores (aquaporins) that allow water to be reabsorbed independent of sodium and chloride.

• Milliequivalent (mEq) - a milliequivalent is the amount of a substance that it takes to combine with 1 mole of hydrogen ions. For example, 1 mole of Cl^- ions will combine with 1 mole of H⁺ ions to form HCl. Therefore, 1 mole of Cl^- ions is equal to one equivalent. If a substance is divalent like calcium (Ca⁺⁺), then only half a mole is required to combine with a mole of a monovalent ion (e.g. CaCl₂). In this case, half a mole of calcium is equal to 1 equivalent. In terms of monovalent serum electrolytes (e.g. Na⁺, Cl^-, K⁺), 1 mmol is equal to 1 milliequivalent so the units of mmol/L and mEq/L can be used interchangeably. See conversions below for information on converting between milligrams, millimoles, and milliequivalents. [3,4,23]

• Mole - one mole of a substance is equal to 6.022 X 10²³ units of the substance which may be atoms, molecules, or ions. The number that defines a mole (6.022 X 10²³) is equal to the number of particles in 12 grams of carbon-12. The atomic weight (or molecular weight if it contains more than one atom) of a substance is the number of grams of a substance that equals 1 mole. For example, sodium has an atomic weight of 23 so one mole of sodium would equal 23 grams. Electrolytes in serum are measured in millimoles per liter (mmol/L). If the electrolyte is monovalent (e.g. Na⁺, Cl^-, K⁺), then its value in mmol/L will be the same in mEq/L and mOsm/L. See conversions below for information on converting between millimoles, milligrams, and milliequivalents. [3,4,23]

• Osmolality / Osmolarity - osmolality is a measure of the total amount of dissolved solutes in a solution. It is expressed as osmoles per kg of water. When it is expressed as osmoles per liter of water, it is called osmolarity. In regards to body fluids, the two terms are interchangeable. Osmolality differs from tonicity in that it includes all solutes dissolved in a solution where tonicity excludes solutes that pass freely across membranes. Solutes that pass freely across cell membranes (e.g. urea) contribute to osmolality, but they do not contribute to tonicity. The normal range of serum osmolality is 270 - 290 mOsm/kg. Serum osmolality can be measured directly or it can be estimated with the following formula:
• Estimated serum osmolality (mOsm/kg) = (2 X serum Na⁺) + (serum glucose / 18) + (BUN / 2.8)
• Where glucose and BUN are in mg/dl
• Measured serum osmolality should not exceed the estimated serum osmolality by more than 10 mOsm/kg. A difference of > 10 mOsm/kg suggests the presence of unmeasured solutes (e.g. alcohol, glycerine, mannitol). The kidneys have a remarkable ability to excrete and retain free water, and they can produce urine with an osmolality that ranges from 50 mOsm/kg (maximum dilution) to 1200 mOsm/kg (maximum concentration). [2,3,4]

• Osmole - an osmole is a measure of the number of moles of a solute that contribute to the osmotic pressure of a solution. Some molecules dissociate in solution while others do not. Molecules that dissociate form more osmotically active solutes than their parent compound. For example, sodium chloride (NaCl) dissociates in water to form Na⁺ and Cl^-. Normal saline (0.9% NaCl solution) is commonly used as an intravenous solution because it is isotonic with plasma which has an osmolarity of 270 - 290 mOsm/L. One liter of normal saline contains 9 grams of NaCl which dissociates in solution into 154 mOsm of Na⁺ and 154 mOsm of Cl^-. The osmolarity of normal saline is therefore equal to the sum of the independent osmoles: 154 mEq Na⁺ + 154 mEq Cl^- = 308 mOsm/L. In actuality, it is slightly less than this because oppositely charged Na⁺ and Cl^- do not behave completely independent of each other so there is a correction factor that brings the effective osmolarity down to 286 mOsm/L. In contrast to NaCl, glucose does not dissociate in solution so 1 mmol/L of glucose is equal to 1 mOsm/L of glucose. [3,4,23]

• Percent solutions - in medicine, most solutions are expressed as weight-in-volume percentages (e.g. 0.9% NaCl, 5% Dextrose). A weight-in-volume percentage is defined as grams of a constituent in 100 ml of solution. That means a 0.9% saline solution has 0.9 grams of NaCl per 100 ml or 9 grams/liter. See percent solution calculations below for information on calculating the number of millimoles and milliequivalents in a percent solution. [23]

• Tonicity - tonicity refers to the amount of dissolved solutes in a solution that cannot pass freely across cell membranes. Solutes that cannot pass freely across cell membranes contribute to the osmotic gradient between intracellular and extracellular compartments. This gradient drives the osmosis of free water. For example, urea passes freely across cell membranes so it distributes itself equally among the intracellular and extracellular compartments, and therefore, it does not affect the osmotic gradient. In contrast, glucose does not pass freely across membranes so increases in serum glucose raise serum tonicity. Solutes that affect tonicity are referred to as "effective osmoles" whereas solutes that do not are called "ineffective osmoles." [3,4,23]

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• CONVERSIONS

• Converting electrolytes from milligrams to millimoles and milliequivalents
• To convert a monovalent electrolyte like Na⁺ or K⁺ from milligrams to millimoles or milliequivalents, the electrolyte is divided by its atomic weight. The atomic weight of an ion is equal to the number of grams of the ion that make up one mole.
• Example 1
• Convert 3600 mg of sodium (Na⁺) to millimoles and milliequivalents
• The atomic weight of Na⁺ is 23 which means there are 23 grams of Na⁺ in a mole
• (3.6 g of Na⁺) / (23 g/mole) = 0.156 moles = 156 millimoles = 156 mEq
• 3600 mg of Na⁺ is equal to 156 millimoles of Na⁺. Since Na⁺ is a monovalent ion, millimoles are equal to milliequivalents.
• Example 2
• Convert 2300 mg of potassium (K⁺) to millimoles and milliequivalents
• The atomic weight of K⁺ is 39 which means there are 39 grams of K⁺ in a mole
• (2.3 g) / (39 g/mole) = 0.05897 moles = 58.97 millimoles = 58.97 mEq
• 2300 mg of K⁺ is equal to 58.97 millimoles of K⁺. Since K⁺ is a monovalent ion, millimoles are equal to milliequivalents.

• Converting electrolytes from millimoles to milligrams and milliequivalents
• To convert an electrolyte from millimoles to milligrams, the electrolyte is multiplied by its atomic weight. To convert millimoles to milliequivalents, multiply millimoles by the electrolyte's valence.
• Example 1
• Convert 0.86 mmol/L of magnesium (Mg⁺⁺) to milligrams and milliequivalents
• The atomic weight of Mg⁺⁺ is 24.3 which means there are 24.3 grams of Mg⁺⁺ in a mole
• 0.86 mmol/L is equal to 0.00086 moles/L | 0.00086 moles/L X 24.3 grams/mole = 0.021 grams/L = 21 mg/L = 2.1 mg/dl
• Since Mg⁺⁺ is a divalent ion, each mole would be equal to two equivalents. Therefore, 0.86 mmol/L X 2 = 1.72 mEq/L.

• Salt calculations
• Electrolytes come in different salts for oral supplementation. For example, potassium is available as potassium chloride, potassium bicarbonate, and potassium gluconate to name a few. The steps below show how to convert milligrams of a salt to millimoles and milliequivalents of an electrolyte.
• Example
• Calculate the milliequivalents of potassium (K⁺) in a 600 mg capsule of potassium chloride
• The atomic weight of K⁺ is 39. The atomic weight of Cl^- is 35.45. The molecular weight of KCl is 74.45 (39 + 35.45).
• KCl is comprised of 52% K⁺ (39/74.45) so 52% of 600 mg is 312 mg of K⁺
• (0.312 g) / (39 g/mole) = 0.008 moles = 8 millimoles = 8 mEq of K⁺
• A 600 mg capsule of KCl contains 8 millimoles of K⁺. Since K⁺ is a monovalent ion, millimoles are equal to milliequivalents.

• Percent solution calculations
• Most electrolytes come in solutions that are expressed as weight-in-volume percentages of the parent salt. For example, normal saline is 0.9% sodium chloride (NaCl) and hypertonic saline is 3% sodium chloride. Weight-in-volume percentages are defined as grams of solute per 100 ml of solution, so 0.9% sodium chloride would have 0.9 grams of NaCl per 100 ml. The steps below show how to calculate the amount of millimoles and milliequivalents of an electrolyte based on a percent solution.
• Example
• Calculate the milliequivalents of sodium (Na⁺) in 1 liter of normal saline (NaCl)
• The atomic weight of Na⁺ is 23. The atomic weight of Cl^- is 35.45. The molecular weight of NaCl is 58.45 (23 + 35.45).
• 0.9% NaCl contains 0.9 grams of NaCl per 100 ml or 9 grams per liter
• NaCl is comprised of 39% Na⁺ (23/58.45) so 39% of 9 grams is 3.54 grams of Na⁺ per liter
• (3.54 g) / (23 g/mole) = 0.154 moles = 154 millimoles = 154 mEq of Na⁺ in 1 liter of normal saline
• One liter of normal saline contains 154 millimoles of Na⁺. Since Na⁺ is a monovalent ion, millimoles are equal to milliequivalents.

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• References [3,22,23]

Estimates of body fluid distribution
Compartment	Estimated volume (Based on total body weight)
Intravascular fluid	0.08 L/kg
Plasma	0.048 L/kg
Extracellular fluid	0.20 L/kg
Intracellular fluid	0.40 L/kg
Whole body fluid (extracellular + intracellular)	0.60 L/kg (men and children) 0.50 L/kg (women and elderly men) 0.45 L/kg (elderly women)
Body fat	0.2 - 0.35 L/kg

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• ELECTROLYTE DISTRIBUTION

• The illustration below shows how electrolytes are distributed between intracellular and extracellular fluids. In general, most cells have a slight excess of anions giving them a net negative charge, and the interstitial fluid has a slight excess of cations giving it a net positive charge. [3,4]

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• POTASSIUM HOMEOSTASIS

• Overview
• Electrolytes are ions that have a positive (cation) or negative charge (anion). Potassium (K⁺) and sodium (Na⁺) are the two main cations found in the human body. Potassium is primarily found inside of cells, and sodium is the main extracellular cation. The Na⁺/K⁺-ATPase pump which is found in the cell membrane of almost all cells is responsible for keeping Na⁺ out of cells and pumping K⁺ into cells.
• Ions like potassium and sodium attract water molecules, so the potassium content of a cell is the main determinant of cell volume just as the sodium content of extracellular fluid is the main determinant of extracellular volume. The distribution of potassium across a cell membrane is important in establishing a resting membrane potential which is involved in muscle contraction and nerve conduction. Low extracellular potassium levels cause membrane hyperpolarization and reduced excitability which can lead to muscle weakness. Elevated extracellular potassium levels cause membrane depolarization and hyperexcitability which can lead to cardiac arrhythmias that are sometimes fatal.
• Potassium is also involved in acid-base homeostasis and the regulation of plasma pH [3,4]

• Potassium homeostasis
• Potassium is found in most foods so the body must eliminate potassium on a regular basis in order to maintain constant levels. The kidneys are the primary organs that control the retention and excretion of potassium. Potassium uptake in the gut is unregulated, so most potassium consumed in the diet is also absorbed. The illustration below shows the normal way in which potassium balance is maintained. [3,4]

• Acute control
• Acutely, the body can shift potassium in and out of cells in response to changes in extracellular pH, osmolality, and certain hormones and medications. In chronic conditions, potassium levels are predominantly controlled by the kidneys, and more complex interactions are at play.
• Acute processes that shift potassium into cells do not represent true potassium deficits. It's important to consider these processes when replacing potassium in order to avoid overcorrection. Having said that, low serum potassium levels are a risk factor for arrhythmias regardless of the etiology.
• The illustration below shows some of the acute processes that can cause potassium shifts [1,2,3,4]

• Aldosterone / renal control
• Under normal conditions, potassium balance is primarily controlled by aldosterone and the delivery of sodium to the distal nephron. Aldosterone stimulates the Na-K ATPase pump in renal collecting ducts, and this causes sodium to be reabsorbed from the tubule in exchange for potassium that is excreted in the urine. The degree to which aldosterone can exert this effect depends upon the amount of sodium that is present in the collecting ducts. The more sodium that is present, the more it is reabsorbed and potassium is lost. If very little sodium is present, the effects of aldosterone are attenuated, and potassium excretion is greatly reduced.
• Aldosterone secretion is stimulated by rising potassium levels and angiotensin II. Angiotensin II levels are controlled by the renin-angiotensin-aldosterone system (RAAS) which is stimulated in response to the following: (1) a decrease in afferent arteriole pressure, (2) decreasing sodium concentrations, (3) increased sympathetic tone (see illustration below).
• Sodium concentrations in the collecting ducts primarily depend upon its reabsorption along the nephron. Under normal conditions, 70% of sodium is reabsorbed in the proximal tubule, 20% in the Loop of Henle, and 6% in the distal tubule. When the body senses a need for sodium retention (e.g. decreased renal perfusion due to CHF, dietary sodium restriction), reabsorption in the proximal tubule can approach 100% and almost no sodium reaches the collecting duct. In contrast, medications like loop and thiazide diuretics block sodium reabsorption along the nephron and increase its delivery to the collecting duct. [3,4,12]

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• HYPOKALEMIA

• Overview
• Most laboratories define hypokalemia as a potassium level < 3.5 mEq/L. Hypokalemia is probably the most common electrolyte abnormality seen in medicine with up to 20% of hospitalized patients and 2 - 3% of outpatients having potassium levels < 3.6 mEq/L. Depending on the population, hypokalemia is seen in 10 - 40% of patients who take thiazide diuretics.
• Most patients with hypokalemia are asymptomatic and suffer no ill effects; however, patients with significant heart disease (e.g. ischemia, heart failure) are at increased risk of arrhythmias even with modest declines in potassium.
• Hypokalemia is typically secondary to an abnormal loss of potassium in the kidneys with the most common cause being medications. Loss of potassium in the stool and abrupt shifts of potassium from the extracellular to the intracellular compartment are other situations that can lead to hypokalemia. Acid-base disorders also have a wide range of effects on potassium that must be considered when treating affected patients. [1,2,3,4,6,7]

• References [1,2,5,6,7,9]

Causes of hypokalemia
Potassium shift into cells - see acute control Increase in plasma pH Insulin May occur with intravenous insulin or IV dextrose infusions that stimulate insulin release Beta-2 adrenergic agonists Epinephrine Pseudoephedrine, phenylpropanolamine - in large amounts Terbutaline Albuterol, levalbuterol One dose of nebulized albuterol reduces serum potassium levels by 0.2 - 0.4 mEq/L, and a second dose within an hour will reduce it by 1 mEq/L. The effects can last for up to 4 hours. Theophylline - stimulates release of sympathetic amines Caffeine - stimulates release of sympathetic amines. The caffeine in 2 cups of coffee can decrease potassium by up to 0.4 mEq/L Verapamil overdose - increases cellular uptake Chloroquine overdose - blocks exit of potassium from cells
Excessive renal loss Thiazide and loop diuretics - see diuretic-induced potassium loss Excessive mineralocorticoid activity - see aldosterone / renal control Adrenal hyperplasia Conn's syndrome (aldosterone-secreting tumor) 17-Hydroxylase deficiency - rare genetic disorder that causes decreased glucocorticoids and sex hormones and increased mineralocorticoid Fludrocortisone High-dose or prolonged therapy with glucocorticoids Some glucocorticoids have mineralocorticoid activity at high doses or with prolonged therapy. See corticosteroid properties. Cushing's syndrome / disease Excess corticosteroids have mineralocorticoid activity High dietary sodium intake - increases delivery of sodium to the distal nephron Licorice Licorice contains a chemical called glycyrrhizic acid that inhibits the 11βHSD2 enzyme thus increasing cortisol and mineralocorticoid activity Diabetic ketoacidosis Renal tubular acidosis type I (Classic distal) and type II (Proximal) Carbonic anhydrase inhibitors (e.g. acetazolamide) Metabolic alkalosis - may occur from diuretics, vomiting, nasogastric suctioning, Bartter and Gitelman syndrome Glucagon - promotes secretion of potassium Antibiotics - intravenous antibiotics that contain a large amount of sodium Penicillin Nafcillin Ampicillin Drugs that deplete magnesium - see hypomagnesemia Aminoglycosides Cisplatin Foscarnet Amphotericin B - may also cause renal tubular acidosis
Other loss Extrarenal loss Vomiting - particularly if metabolic alkalosis occurs. Only a small amount of potassium is lost in vomitus. Diarrhea / Laxatives / Enemas - colonic fluid contains about 30 mEq/L of potassium so profuse diarrhea can cause significant loss Potassium-binding resins (e.g. Kayexalate, Paritomer) Dilutional IV fluids without potassium Decreased intake Alcoholism Eating disorders (e.g. anorexia) Hypomagnesemia - see hypomagnesemia Hyperthyroidism Hyperthyroidism is a rare cause of hypokalemia. Mostly seen in Asian patients. Mechanism is unclear but may occur from thyroid hormone stimulating the Na-K ATPase pump. Treatment of severe pernicious anemia Rapid uptake of potassium by newly formed RBCs can cause hypokalemia Familial hypokalemic periodic paralysis Rare disorder marked by sudden onset of weakness and hypokalemia. Hypokalemia occurs secondary to skeletal muscle uptake. Attacks may be precipitated by high carbohydrate intake or exertion. Transfusion with previously frozen RBCs - transfused RBCs may take up potassium and cause hypokalemia Pseudohypokalemia Leukocytosis - significant leukocytosis (> 75,000 WBCs/mm3) can cause pseudohypokalemia when WBCs take up potassium in the sample Recent IV insulin administration Storage of blood samples at high room temperature (seasonal pseudohypokalemia) - heat stimulates Na-K ATPase activity

• Symptoms / ECG changes
• Most patients with potassium levels > 2.5 mEq/L are asymptomatic. When symptoms occur, they are usually nonspecific and include weakness, fatigue, constipation, and exercise intolerance. With severe hypokalemia, muscle cramps, rhabdomyolysis, and paralysis can occur.
• ECG changes may be seen once the potassium level falls below 3.0 mEq/L, although many patients in this range will still have no findings. The absence of ECG changes should not be interpreted as low arrhythmia risk since no ECG findings or subtle changes can precede significant arrhythmias in some hypokalemic patients, particularly those with significant heart disease.
• ECG changes seen with hypokalemia include the following:
• Flattening of the T-waves - decreased T-wave amplitude is the earliest signs of hypokalemia
• ST-segment depression, T-wave inversion, PR-interval prolongation - occurs after T-wave flattening
• U-waves - U waves are positive deflections after the T-wave. In severe hypokalemia, the T-wave and U-waves fuse forming one giant wave.
• Ventricular and atrial arrhythmias - end result in severe cases [1,6,7]

• Diagnosis
• In the majority of cases, the etiology of hypokalemia is obvious (e.g. diuretic use, vomiting, DKA). When the cause is not easily identified, diagnostic testing may be necessary to help pinpoint the underlying problem. The steps detailed below can serve as a guide for working up hypokalemia.

• References [5,6,7,11]

Steps for evaluating hypokalemia
Step 1 - measure urinary potassium excretion Measuring urine potassium is the first and most important step in analyzing hypokalemia because it helps to determine if potassium loss is renal or extrarenal. The most direct method for measuring urinary potassium excretion is with a 24-hour urine. 24-hour urine collections are tedious, so a spot urine potassium or a spot urine potassium-to-creatinine ratio is often performed instead. All 3 methods are discussed below. 24-hour urine potassium - this is the best method because it directly measures the amount of potassium excreted in a day. Method is tedious, particularly on an outpatient basis. A 24-hour creatinine should also be measured to ensure that a full and accurate sample has been obtained. 24-hour potassium < 20 mEq - suggests proper conservation of potassium by the kidneys and makes an extrarenal source of potassium loss more likely 24-hour potassium > 20 mEq - suggests renal potassium wasting Urine potassium-to-creatinine ratio - this test is easier to perform than a 24-hour urine because it only requires that the patient give a urine sample. Creatinine is excreted at a constant rate, so taking the ratio of potassium to creatinine in the sample helps to correct for variations in urine dilution. Ratio ≤ 1.5 mEq/mmol (13 mEq/gram) - suggests proper conservation of potassium by the kidneys and makes an extrarenal source of potassium loss more likely Ratio > 1.5 mEq/mmol (13 mEq/gram) - suggests renal potassium wasting Spot urine potassium - a spot urine potassium is easy to perform. The main drawback to the test is that it does not correct for variations in urine dilution. A urine osmolality can be drawn with a spot potassium to evaluate urine concentration. High urine osmolality (> 700 mOsm/kg) suggests that a high potassium may be secondary to concentrated urine as opposed to excessive potassium excretion. Spot potassium < 20 mEq/L - suggests proper conservation of potassium by the kidneys and makes an extrarenal source of potassium loss more likely Spot potassium > 40 mEq/L - suggests renal potassium wasting
Step 2 - based on results from Step 1, consider the following: Renal potassium wasting - see causes of renal potassium wasting Nonrenal potassium loss - see other causes and potassium shift into cells
Step 3 - for renal potassium loss, consider the following testing: Arterial blood gas (ABG) - an ABG is necessary to identify metabolic acidosis or alkalosis Alkalosis - consider diuretics, vomiting, nasogastric suctioning, excessive mineralocorticoid activity, Bartter syndrome, and Gitelman syndrome Acidosis - consider renal tubular acidosis type I and II, DKA, and carbonic anhydrase inhibitors Serum Magnesium - hypomagnesemia can contribute to renal potassium loss Urine chloride - in patients with metabolic alkalosis, urine chloride measurements can help determine the etiology Spot urine chloride < 20 mEq/L or 24-hour urine chloride < 10 mEq - diuretics, vomiting, nasogastric suctioning Spot urine chloride > 40 mEq/L or 24-hour urine chloride > 20 mEq - excessive mineralocorticoid activity, Bartter syndrome, and Gitelman syndrome Urine sodium - a spot urine sodium level that is < 20 mEq/L with a high urine potassium suggests excessive mineralocorticoid activity Aldosterone and renin levels - elevated aldosterone levels are consistent with mineralocorticoid excess. The aldosterone-to-renin ratio (ARR) can help identify if the hyperaldosteronism is primary or secondary. ARR > 30 - consistent with primary aldosteronism (Conn's syndrome) ARR < 10 - consistent with secondary aldosteronism which is caused by decreased renal blood flow (e.g. dehydration, CHF, anasarca) Cortisol level - a high cortisol level suggests glucocorticoid excess (e.g. Cushing's syndrome) may be the cause of excessive mineralocorticoid activity

• Diuretic-induced hypokalemia
• In diuretic-induced hypokalemia, thiazide and loop diuretics block the reabsorption of sodium along the nephron and thus increase its delivery to the distal collecting ducts. High sodium concentrations in the distal collecting duct enhance the effects of aldosterone and create an electrochemical gradient that favors the excretion of potassium.
• Chronic use of thiazide and loop diuretics can also lead to metabolic alkalosis which further enhances potassium loss (see metabolic alkalosis below) [1,2,3,4]

• Metabolic alkalosis
• Metabolic alkalosis is typically caused by chloride loss which drives processes that lead to hypokalemia. Chloride loss can occur in a number of conditions including nasogastric suctioning, vomiting, and genetic defects in Na-Cl renal transporters (Bartter and Gitelman syndromes). One of the most common causes of chloride loss is the chronic use of thiazide and loop diuretics. Diuretics cause a mild or moderate metabolic alkalosis (HCO₃ 28 - 36 mEq/L) through chloride loss and a process that is often referred to as "contraction alkalosis." In contraction alkalosis, loss of fluid causes extracellular volume to "contract" around a constant amount of bicarbonate. This leads to higher bicarbonate concentrations and alkalosis.
• Acutely, metabolic alkalosis causes potassium to shift into cells in exchange for hydrogen ions. Over time, compensatory mechanisms in the kidney take over and potassium is lost in the urine. The illustration below describes the main processes that drive potassium loss in metabolic alkalosis. [1,2,3,4]

• Metabolic acidosis
• Metabolic acidosis can lead to hypokalemia in some cases. Acutely, acidosis causes serum potassium levels to rise as hydrogen ions are taken up by cells in exchange for potassium. For every 0.1 decrease in arterial pH, potassium levels increase by approximately 0.6 mEq/L. As the acidosis persists, renal processes predominate and hypokalemia occurs. The mechanisms by which hypokalemia occurs in metabolic acidosis are not completely understood. Some common causes of metabolic acidosis and the proposed mechanism for hypokalemia are given below. [1,2,3,4]

• Diabetic ketoacidosis (DKA) - DKA is thought to cause hypokalemia through the following two mechanisms: (1) osmotic diuresis induced by glycosuria increases the delivery of sodium to the distal nephron where it is taken up in exchange for potassium, (2) hyperosmolar fluid in the collecting duct pulls water into the lumen causing the concentration of potassium to decrease; lower potassium concentrations in the lumen favor the diffusion of potassium from tubular cells into the lumen. Serum potassium levels often do not reflect true potassium deficits in prolonged DKA because hypertonicity, decreased pH, and insulin deficiency impede the uptake of potassium into cells. When fluids and insulin are given to treat DKA, profound hypokalemia is often unmasked. [1]

• Renal tubular acidosis (RTA) - renal tubular acidosis is a group of conditions where the kidneys are ineffective at eliminating acids and retaining bicarbonate. RTA type I and type II can cause profound hypokalemia. Proposed mechanisms by which hypokalemia occurs include the following: (1) increased aldosterone activity secondary to sodium loss, (2) passive diffusion of potassium into the collecting duct, (3) decreased proximal reabsorption of potassium secondary to acidemia and hypocapnia. [1,2,10]

• Carbonic anhydrase inhibitors (e.g. acetazolamide) - carbonic anhydrase inhibitors block the reabsorption of bicarbonate in the proximal tubule. This decreases the production of hydrogen ions and the subsequent reabsorption of sodium through the Na⁺/H⁺ exchanger. More sodium is delivered to the distal tubule where aldosterone stimulates its reabsorption in exchange for potassium. See carbonic anhydrase and acetazolamide for more. [1,2,3,4]

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• HYPOKALEMIA TREATMENT

• Overview
• Low serum potassium levels, whether they are from true deficits or intracellular shifts, need to be addressed because the risk of arrhythmias is increased regardless of the etiology. That being said, correcting hypokalemia must be done cautiously, because hyperkalemia has the same arrhythmogenic potential as hypokalemia.
• When treating hypokalemia, one must consider the underlying pathology because the serum potassium level is not always a true reflection of total body potassium stores. For example, in diabetic ketoacidosis, potassium levels are often normal even though potassium stores are severely depleted. This occurs because hypertonicity, decreased pH, and insulin deficiency impede the uptake of potassium into cells. When fluids and insulin are given to treat DKA, profound hypokalemia is often unmasked. In another example, patients receiving nebulized albuterol may have low serum potassium levels when no true deficit exists. This occurs because albuterol stimulates the uptake of potassium into cells.
• The information below offers some guidance on potassium replacement, but every case must be considered individually because dietary intake, medications (e.g. ACE inhibitors, aldosterone antagonists), and medical problems (e.g. heart disease, kidney disease) must all be taken into account when trying to achieve a proper balance between adequate correction and overcorrection. [1,2,3,4]

• Potassium < 2.5 mEq/L
• In general, IV potassium replacement should be given to all individuals who have a potassium level < 2.5 mEq/L
• IV potassium can be given at a rate of 10 - 20 mEq/hour. In extreme cases, 40 mEq/hour can be given through a central line under close monitoring. [6,7]

• Potassium 2.5 - 2.9 mEq/L
• Patients with significant heart disease should receive IV potassium replacement for levels < 3.0 mEq/L
• Otherwise healthy patients with normal ECG and mild to no symptoms can receive oral therapy in most cases [6]

• Potassium ≥ 3 mEq/L
• In most cases, patients with potassium levels ≥ 3 mEq/L can be treated with oral therapy
• Patients with significant cardiac disease, symptoms, and/or ECG changes should be considered for more aggressive therapy [6]

• Oral replacement recommendations
• Oral potassium is the safest and preferred method of replacing potassium. Under normal conditions, a reduction of 0.3 mEq/L in serum potassium represents a 100 mEq decrease in total body potassium stores. That being said, it's important to remember that serum potassium levels are not always an accurate reflection of potassium stores, and because of this, there is no straightforward, one-size-fits-all method for replacing potassium. Some general principles of oral potassium replacement are given below.
• General principles of oral potassium replacement
• Hypokalemia treatment - hypokalemia can typically be treated with 40 - 100 mEq of potassium supplements per day. The length of therapy will depend on the deficit, but may last days to weeks.
• Hypokalemia prevention - for patients with ongoing potassium losses (e.g. diuretic therapy), hypokalemia can typically be prevented with 20 mEq of potassium supplements per day.
• Diuretic-induced hypokalemia - options for treatment/prevention of diuretic-induced hypokalemia include the following:
• Addition of potassium-sparing diuretics (ENaC inhibitors)
• Concomitant aldosterone antagonists
• Concomitant ACE inhibitors or ARBs
• Potassium supplements
• Low-sodium diet (< 1500 mg of sodium a day)
• Dietary potassium - increases in dietary potassium (see dietary potassium below) can help improve hypokalemia, but dietary potassium is almost entirely potassium phosphate, and it will not be effective in conditions where chloride depletion coexists (e.g. diuretic therapy, vomiting). Potassium chloride supplements should be added to dietary measures in these cases.
• Hypomagnesemia - low magnesium levels impair the ability of the body to retain potassium. Magnesium replacement may be necessary in some patients with hypokalemia. [1,6,7,8]

• Potassium supplements
• Oral potassium supplements come in 4 different salts: chloride, bicarbonate, citrate, and gluconate. Potassium chloride is the preferred replacement form in most cases because it contains chloride which is frequently deficient in hypokalemia. Potassium citrate is mostly used to prevent kidney stones, and potassium bicarbonate is found in antacids. Potassium gluconate is present in a number of over-the-counter supplements.
• Potassium content can be expressed in three different ways: milligrams (mg), milliequivalents (mEq), and millimoles (mmol). One milliequivalent of potassium is equal to one millimole. When converting between milliequivalents, millimoles, and milligrams, the calculation depends on the potassium salt (see salt calculations above). The table below details the available potassium supplements along with their conversion ratios.

• Dietary potassium
• Potassium is found in most foods, primarily in the form of potassium phosphate. Increasing dietary potassium can help to treat and prevent hypokalemia, but most conditions that lead to hypokalemia (e.g. diuretics) also involve the loss of chloride, so potassium chloride supplements are recommended.
• For healthy adults, the World Health Organization recommends potassium intake of at least 90 mEq/day (3510 mg) while the 2015 Dietary Guidelines for Americans recommends 120 mEq/day (4700 mg). To convert the milligrams of potassium in food to milliequivalents, divide milligrams by 39.
• The potassium content of a number of common foods are given in the table below. Salt substitutes (e.g. No-Salt) also contain a large amount of potassium chloride and should be used cautiously in patients who are at risk for hyperkalemia. The potassium content of almost any food can be found by searching the USDA food database.

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• HYPERKALEMIA

• Overview
• In adults, hyperkalemia is defined as a potassium level > 5.2 mEq/L. It is seen in up to 10% of hospitalized patients and 1% of outpatients. A number of conditions can lead to hyperkalemia, but the most common cause by far is the use of drugs that inhibit the RAAS; up to 10% of outpatients who are prescribed ACE inhibitors experience hyperkalemia within a year. Like hypokalemia, hyperkalemia can lead to cardiac arrhythmias and death if untreated.
• The kidneys are the primary regulators of potassium balance, and there are three main processes that can reduce their ability to excrete potassium: (1) decreased delivery of sodium to the distal nephron, (2) decreased aldosterone activity, (3) diseases that damage the distal collecting duct and impair its ability to secrete potassium. The processes that control aldosterone secretion and delivery of sodium to the distal nephron are discussed above (see aldosterone/renal control). Diseases that impair potassium secretion in the distal collecting duct include diabetic nephropathy, lupus, sickle cell disease, lower urinary tract obstruction, and renal tubular acidosis to name a few. [7,12,13]

• References [7,13,9]

Causes of hyperkalemia
Potassium shift out of cells - see acute control Decrease in plasma pH - metabolic acidosis Insulin deficiency Tissue ischemia / trauma / toxicity Burns Rhabdomyolysis Cellular damage / lysis Tumor lysis syndrome Hemolytic anemia Large hematomas Transfusion reactions Medications Digoxin - can inhibit the Na-K ATPase pump Beta-adrenergic blockers Somatostatin Succinylcholine Hyperosmolality - hyperglycemia, mannitol Strenuous exercise
Decreased renal excretion Decreased mineralocorticoid production - see aldosterone / renal control Addison disease - condition where adrenal glands produce insufficient amount of corticosteroids Heparin - blocks production of aldosterone in adrenal gland Ketoconazole - blocks production of aldosterone in adrenal gland RAAS inhibitors ACE inhibitors Angiotensin II receptor blockers (ARBs) Renin inhibitors (aliskiren) Aldosterone antagonists (spironolactone) NSAIDs Epithelial sodium channel (ENaC) inhibitors - see aldosterone / renal control Amiloride Triamterene Trimethoprim - has similar structure and action as amiloride Pentamidine Other medications Tacrolimus - suppresses renin release and interferes with potassium excretion in the collecting duct Cyclosporine - suppresses renin release and interferes with potassium excretion in the collecting duct Renal tubular cell damage Amyloidosis Diabetic nephropathy HIV / AIDS Kidney transplant rejection Lower urinary tract obstruction Sickle cell disease Systemic lupus erythematosus Decreased renal perfusion CHF Cirrhosis Renal artery stenosis
Other Increased intake (foods and supplements) Herbs high in potassium - alfalfa, dandelion, horsetail, nettle High potassium foods - see dietary potassium Noni juice (56 mEq/Liter) Salt substitutes (e.g. No-Salt) - 16.4 mEq per 1/4 tsp Medications Penicillin G potassium (1.68 mEq per 1 million units) Potassium supplements Red blood cell transfusions - leakage of potassium into supernatant due to decreased Na-K ATPase activity Pseudohyperkalemia Mechanical hemolysis - can occur if tourniquet during blood draw is too tight or left on too long. Also may occur if sample is left sitting too long. Excessive milking of extremities - seen in infant heel and finger sticks. Introduces interstitial fluid into sample. Fist clenching during sample draw - can cause hemolysis and an acidotic sample Potassium-containing IV infusions - if blood is drawn upstream of the infusion site Thrombocytosis (> 500,000/µL ) - for every 100,000/µL elevation in platelet count, serum potassium increases by 0.15 mEq/L. This occurs secondary to potassium release from platelets during the clotting process. Whole blood and plasma potassium levels (obtained from a heparinized sample) are not affected by thrombocytosis and should be drawn to confirm hyperkalemia in patients with platelet counts > 500,000/µL. Leukocytosis (> 70,000/µL) - elevated serum potassium may occur secondary to potassium release from WBCs during the clotting process. Whole blood and plasma potassium levels (obtained from a heparinized sample) are not affected by leukocytosis and should be drawn to confirm hyperkalemia in patients with WBC counts > 70,000/µL. Reverse pseudohyperkalemia - reverse pseudohyperkalemia is a phenomenon where plasma potassium levels are spuriously higher than serum potassium levels. It can occur in patients with leukemia because leukemic leukocytes are fragile and can release potassium during processing. Measuring potassium levels from an arterial blood gas sample can prevent reverse pseudohyperkalemia.

• Symptoms / ECG changes
• Most patients with hyperkalemia are asymptomatic. When levels rise above 6.5 mEq/L, some patients may experience nonspecific symptoms such as weakness, fatigue, palpitations, and paresthesias. Severe hyperkalemia (≥ 7 mEq/L) can cause respiratory paralysis and cardiac arrest.
• ECG changes often correlate with the degree of hyperkalemia and are presented below. In patients with heart disease who have abnormal baseline ECGs, bradycardia may be the only new finding.


• Potassium 5.5 - 6.5 mEq/L
• Peaked T-waves
• Shortened QT-interval
• ST-segment depression
• Potassium 6.5 - 8 mEq/L
• Peaked T-waves
• Prolonged PR interval
• Diminished or absent P waves
• QRS widening
• Amplified R wave
• Potassium > 8 mEq/L
• Absent P waves
• Progressive QRS widening
• Bundle branch blocks
• Sine wave pattern - fusion of widened QRS with T-wave
• Ventricular fibrillation or asystole [13]

• Diagnosis
• In most cases, the cause of hyperkalemia is obvious (e.g. medications, kidney failure). When the cause is not apparent, certain laboratories (see below) can be helpful in determining an etiology. In cases where the hyperkalemia is unexpected, potassium levels should be rechecked because spurious causes of hyperkalemia are common (see pseudohyperkalemia above)

• References [7,11,12,13]

Laboratories for evaluating hyperkalemia

Serum creatinine and GFR / CrCl Since the kidneys are the primary site of potassium excretion, decreased renal function is a major cause of hyperkalemia In chronic kidney disease, hyperkalemia does not typically occur until the GFR falls below 30 ml/min. Patients who have other risk factors for decreased renal function (e.g. CHF, diabetes, advanced age) may experience hyperkalemia at levels > 30 ml/min. These patients are also frequently prescribed RAAS inhibitors which compound the risk. See GFR / CrCl and serum creatinine for a review of these measures Urine potassium Measuring urine potassium can help to determine if the kidneys are excreting potassium appropriately. The most direct method for measuring urinary potassium excretion is with a 24-hour urine. 24-hour urine collections are tedious, so a spot urine potassium or a spot urine potassium-to-creatinine ratio is often performed instead. All 3 methods are discussed below. 24-hour urine potassium - this is the best method because it directly measures the amount of potassium excreted in a day. Method is tedious, particularly on an outpatient basis. A 24-hour creatinine should also be measured to ensure that a full and accurate sample has been obtained. 24-hour potassium < 20 mEq - suggests impaired renal excretion 24-hour potassium > 20 mEq - suggests appropriate renal elimination Urine potassium-to-creatinine ratio - this test is easier to perform than a 24-hour urine because it only requires that the patient give a urine sample. Creatinine is excreted at a constant rate, so taking the ratio of potassium to creatinine in the sample helps to correct for variations in urine dilution. Ratio ≤ 1.5 mEq/mmol (13 mEq/gram) - suggests impaired renal excretion Ratio > 1.5 mEq/mmol (13 mEq/gram) - suggests appropriate renal elimination Spot urine potassium - a spot urine potassium is easy to perform. The main drawback to the test is that it does not correct for variations in urine dilution. A urine osmolality can be drawn with a spot potassium to evaluate urine concentration. High urine osmolality (> 700 mOsm/kg) suggests that a high potassium may be secondary to concentrated urine as opposed to appropriate potassium excretion. Spot potassium < 20 mEq/L - suggests impaired renal excretion Spot potassium > 40 mEq/L - suggests appropriate renal elimination Urine sodium Spot urine sodium > 25 mEq/L - suggests decreased mineralocorticoid activity or direct renal cell damage Spot urine sodium < 25 mEq/L - suggests appropriate mineralocorticoid activity. Consider decreased renal perfusion (e.g. cirrhosis, CHF). Other labs that may be helpful depending on the presentation / risk factors Arterial blood gas (ABG) - an ABG can identify acidosis Serum glucose - to look for diabetes and insulin deficiency Urinalysis - to look for nephropathy and glomerulonephritis Serum cortisol and aldosterone levels - to look for adrenal insufficiency Serum uric acid and phosphorus - elevated in tumor lysis syndrome Serum creatinine phosphokinase (CPK) - to look for rhabdomyolysis Urine myoglobin - present in rhabdomyolysis and crush injuries Potassium level from plasma or whole blood - if thrombocytosis or leukocytosis are present (see pseudohyperkalemia above) Potassium level from ABG - in patients with leukemia to rule out reverse pseudohyperkalemia (see pseudohyperkalemia above)

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• HYPERKALEMIA TREATMENT

• Overview
• Severe hyperkalemia can lead to life-threatening arrhythmias so it is important to address elevated potassium levels. Medications are a significant cause of hyperkalemia so in many cases, adjusting drug therapy is all that needs to be done. Some conditions like chronic renal failure require ongoing treatment, and severe, acute elevations require immediate attention.

• Potassium levels
• There are no consensus guidelines that define an "emergent potassium level," nor is there a standardized approach to treatment. The ranges below offer some guidance on treating hyperkalemia, but it's important to keep in mind that every case must be considered individually because the rate of rise, ECG changes, and etiology all play an important role in determining how aggressive therapy should be.
• Potassium 5 - 5.9 mEq/L - elevations in this range are considered mild and typically can be treated with medication adjustments
• Potassium 6 - 6.4 mEq/L - elevations in this range are considered moderate, and in most cases, hospital admission is recommended
• Potassium 6.5 - 6.9 mEq/L - elevations in this range are considered moderate-high. Hospital admission with ECG monitoring is recommended along with acute treatment.
• Potassium ≥ 7.0 mEq/L - elevations in this range are considered severe. Prompt acute treatment is recommended along with hospital admission. [13,14,15]

• Acute treatment
• Acute treatment of hyperkalemia is indicated when levels exceed 6.5 mEq/L, and the risk of arrhythmia is increased. Insulin and albuterol act quickly to shift potassium into cells and calcium is used to stabilize the cardiac transmembrane potential. Nuances of each treatment are discussed below.
• Calcium gluconate 10%
• Dosing: 1 ampule (1 gm) by slow IV bolus (1 - 2 min). May be repeated after 5 minutes if ECG does not improve.
• Onset of action: < 3 minutes
• Duration of effect: 20 - 50 minutes
• Other: if digitalis toxicity is suspected, use caution or avoid
• Regular insulin
• Dosing: 0.1 unit/kg (max 10 units) by IV bolus. If serum glucose is < 250 mg/dl, give 50 - 100 ml bolus of 50% dextrose prior to insulin. Another regimen is 20 units by IV infusion over 1 hour together with dextrose 60 g.
• Decrease in potassium: 0.6 - 1.2 mEq/L after 1 hour
• Onset of action: 15 minutes
• Duration of effect: 4 hours
• Other: monitor serum glucose hourly for at least 3 hours
• Albuterol
• Dosing: 10 - 20 mg via nebulizer
• Decrease in potassium: 0.5 - 1 mEq/L
• Onset of action: within 30 minutes
• Duration of effect: maximum effect seen at 90 minutes
• Other: more effective when used with insulin. Dose is much larger than what is used in bronchospasm and may precipitate arrhythmias in patients with heart disease. [13,15]

• RAAS inhibitor-induced hyperkalemia
• Hyperkalemia is a common side effect of RAAS inhibitors, occurring in up to 10% of people prescribed these drugs. Most people with normal renal function tolerate RAAS inhibitors fine, but patients with diabetes, CHF, and chronic kidney disease are at greater risk for hyperkalemia. That being said, RAAS inhibitors have consistently been shown to improve outcomes in all of these conditions. Providers are therefore left with the task of balancing the benefits of RAAS inhibitor therapy with the risks of hyperkalemia. The recommendations presented below provide some guidance in treating RAAS inhibitor-induced hyperkalemia.
• Recommendations for treating RAAS inhibitor-induced hyperkalemia:
• Inquire about and discontinue the following if applicable: high potassium foods, salt substitutes, herbs and supplements that are high in potassium, NSAIDs
• If possible, discontinue medications that can raise potassium levels (e.g. ENaC inhibitors, tacrolimus, cyclosporine, ketoconazole)
• Prescribe a thiazide or loop diuretic (loop diuretics are preferred if GFR is < 30 ml/min)
• In patients with chronic kidney disease and metabolic acidosis (HCO3 < 22 mEq/L), prescribe one to two 650 mg tablet(s) of sodium bicarbonate twice a day. Each tablet contains 8 mEq of sodium bicarbonate. Alternatively, 1/2 – 1 teaspoon of baking soda daily provides 25 – 50 mEq of sodium bicarbonate.
• If potassium is < 5.5 mEq/L, decrease dose of RAAS inhibitor. If patient is taking multiple RAAS inhibitors, discontinue one. Recheck potassium in 1 week.
• When prescribing spironolactone, dose should not exceed 25 mg when given with an ACE inhibitor or ARB. Do not combine spironolactone with an ACE inhibitor or ARB if GFR is < 30 ml/min.
• If potassium is > 5.5 mEq/L despite the above steps, discontinue RAAS inhibitor [12]

• Chronic kidney disease
• Chronic kidney disease is a major risk factor for hyperkalemia, and given the fact that it is a sequelae of common conditions like diabetes and hypertension, it is also quite prevalent (up to 15% of U.S. adults). Kidney disease in itself does not typically cause hyperkalemia until the GFR falls below 30 ml/min. However, many patients with CKD are treated with RAAS inhibitors, and they have coexisting conditions (e.g. CHF) that heighten their risk. The recommendations below offer some guidance in preventing and treating hyperkalemia in chronic kidney disease.
• Recommendations for treating and preventing hyperkalemia in chronic kidney disease:
• Target serum potassium levels in CKD should be 4 - 4.5 mEq/L. Levels ≥ 5 mEq/L should be followed closely and strategies to prevent further rise should be implemented.
• Dietary potassium restriction (2 - 3 grams/day or 51 - 77 mEq/day) should be started when potassium levels are > 5 mEq/L
• Sodium bicarbonate (3 - 5 grams/day) is indicated when metabolic acidosis is present (HCO3 < 22 mEq/L)
• Loop diuretic should be added or their dose increased when appropriate
• Prescribe potassium binders (see below) when other measures fail [14,15]

• Potassium binders
• Sodium polystyrene sulfonate (Kayexalate®) - sodium polystyrene sulfonate (SPS) is a cation exchange resin that binds potassium in the distal large intestine. SPS can be given orally or as a rectal enema. SPS swells when it comes in contact with water, and in large doses, it can increase the risk of intestinal obstruction. Because of this and to speed delivery to the distal colon, SPS is commonly given with sorbitol, an osmotic cathartic. The effects of SPS are not seen for 2 hours so it is not useful for the acute treatment of hyperkalemia. Daily doses of 15 - 30 grams are sometimes used to control mild-to-moderate hyperkalemia (5 - 5.9 mEq/L) in CKD. A small trial (N=33) in patients with CKD (average GFR 18 ml/min) and hyperkalemia (average potassium 5.24 mEq/L) found that SPS 30 grams once daily for 7 days lowered serum potassium levels by 1.04 mEq/L when compared to placebo. [PMID 26576619]. SPS should be avoided in patients who are at risk for bowel obstruction or perforation. [SPS PI] [13,14,16]

• Patiromer (Veltassa®) - patiromer is a non-absorbed cation exchange polymer that binds potassium in the intestines and increases its excretion. Patiromer comes as a powder for suspension and the starting dose is 8.4 grams once daily. It can be titrated at a minimum of weekly intervals to a maximum of 25.2 grams once daily. Unlike Kayexalate, patiromer does not swell appreciably when it comes in contact with water so it does not appear to carry the same risk of intestinal obstruction. It can cause magnesium loss and lead to hypomagnesemia in up to 8% of patients. In a study of patients with CKD treated with RAAS inhibitors (average baseline potassium of 5.6 mEq/L), patiromer decreased potassium levels by 1.01 mEq/L after 4 weeks. [PMID 25415805]. In another study, patiromer was shown to be safe and effective for up to 52 weeks. [PMID 26172895] [Veltassa PI] [13,14,16]

• Sodium zirconium cyclosilicate (Lokelma®) - Lokelma is a non-absorbed zirconium silicate that binds potassium in the intestine and increases its excretion. Lokelma comes as a powder for suspension, and the starting dose for hyperkalemia is 10 grams three times a day for up to 48 hours. After that, the recommended maintenance dose is 10 grams once daily with a maximum of 15 grams once daily. Lokelma contains a significant amount of sodium (400 mg per 5 grams), and in trials, more patients on Lokelma experienced edema (5.9% with 10 g/day and 16.1% with 15 g/day) when compared to placebo (2.4%). In a study of patients with an average baseline potassium of 5.6 mEq/L, Lokelma lowered serum potassium levels to 4.5 mEq/L after 48 hours and was shown to be effective at maintaining normal potassium levels for up to 28 days. [PMID 25402495] [Lokelma PI] [13,14,16]

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• SODIUM HOMEOSTASIS

• Overview
• Sodium is the most abundant extracellular cation, and it is the primary determinant of serum osmolality which makes it the most important solute in the regulation of fluid balance. Sodium homeostasis is depicted in the illustration below.

• Sodium regulation
• Given its importance in controlling body fluid status, it's no surprise that sodium is under the influence of a number of processes. The most important of these processes are outlined below.

• Antidiuretic hormone (ADH) - antidiuretic hormone, also called "vasopressin" and "arginine vasopressin," is a hormone released by the posterior pituitary gland in response to stimuli from osmoreceptors and baroreceptors. The main action of ADH is in the renal collecting duct where it stimulates the reabsorption of free water (water free of solutes).

• Serum osmolality - serum osmolality is primarily a product of sodium and its accompanying anions, chloride and bicarbonate. Osmoreceptors in the hypothalamus sense serum osmolality and use it as a measure of body fluid status. When serum osmolality is high (≥ 295 mOsm/kg), osmoreceptors promote water conservation by stimulating ADH release and thirst. When osmolality is low (< 275 mOsm/kg), osmoreceptors inhibit ADH release. Serum osmolality can be measured directly or it can be estimated with the formula below. Measured serum osmolality should not exceed the estimated serum osmolality by more than 10 mOsm/kg. A difference of > 10 mOsm/kg suggests the presence of unmeasured solutes (e.g. alcohol, glycerine, mannitol).
• Estimated serum osmolality (mOsm/kg) = (2 X serum Na⁺) + (serum glucose / 18) + (BUN / 2.8)
• Where sodium is in mEq and glucose and BUN are in mg/dl

• Baroreceptors - Baroreceptors located in the carotid sinus, aortic arch, cardiac atrium, hypothalamus, and kidneys sense changes in vascular pressure. When pressure is low, they stimulate the conservation of water through ADH release and the conservation of sodium through renin release. When pressure is high, they inhibit ADH and renin release.

• Renin-angiotensin-aldosterone system (RAAS) - the RAAS (see aldosterone / kidney control above) is stimulated by decreased renal perfusion, decreased sodium levels, and increased sympathetic tone. One of its main effects is to promote the reabsorption of sodium along the nephron.

• Natriuretic peptides - natriuretic peptides are proteins released by the atria (ANP) and ventricles (BNP) of the heart. They are released in response to distension of these chambers from volume overload. Natriuretic peptides counteract the effects of renin and ADH in the kidneys, and thus, they promote the excretion of sodium and water.

• Renal excretion of sodium and water - The kidneys are the primary site of sodium and water regulation. Sodium and water pass freely into the renal tubule and they are absorbed at different rates along the nephron. Water tends to follow sodium when it is reabsorbed, but permeability to water along the nephron differs, so they are not reabsorbed equally. In the collecting duct, ADH controls the amount of water that is reabsorbed independent of sodium reabsorption. The kidneys are capable of excreting and conserving a large amount of water, and they can produce urine that varies in osmolality from 50 mOsm/kg to 1200 mOsm/kg.
• Reabsorption of sodium and water along the nephron under normal conditions
• Proximal convoluted tubule: 70% of sodium and 70% of water
• Loop of Henle: 20% of sodium and 10% of water
• Distal convoluted tubule: 6% of sodium and 0% of water
• Collecting ducts: 3% of sodium and 19% of water

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• HYPONATREMIA

• Overview
• Hyponatremia is defined as a plasma sodium level < 135 mEq/L. It is seen in up to 35% of hospitalized patients and around 2% of outpatients.
• Because sodium is a major determinant of extracellular osmolality, hyponatremia typically leads to concurrent serum hypotonicity. Less frequently, it is seen in the setting of serum isotonicity and hypertonicity. In hypotonic hyponatremia, body fluid status is important to consider, because it can help to identify the underlying disorder. The table below groups causes of hyponatremia by tonicity and volume status. [19,20]

• References [2,19,20,21,22]

Hypotonic hyponatremia (serum osmolality < 275 mOsm/kg)
Hypovolemic causes - total body water decreases more than the decrease in total body sodium Gastrointestinal fluid loss (diarrhea or vomiting) Diuretic therapy Thiazide diuretics are prone to cause hyponatremia with long-term use because they promote sodium excretion while reducing the diluting capacity of the nephron. In contrast, loop diuretics promote both sodium excretion and urine dilution. This occurs because the hyperosmolarity of the medullary region of the kidney that is responsible for water reabsorption in the collecting duct is mostly a product of sodium, potassium, and chloride that is reabsorbed in the ascending Loop of Henle by the Na-K-2Cl transporter. Loop diuretics block this transporter causing medullary osmolality to decrease. Reduced medullary osmolality causes less free water to be drawn from the collecting duct. Thiazide diuretics do not lower the medullary osmolality, and therefore, free water reabsorption remains normal while solute excretion is increased. Salt-wasting nephropathies - rare sequelae of interstitial kidney disease, polycystic kidney disease, and urinary obstruction Cerebral salt wasting - condition where intracranial disorders (e.g. subarachnoid hemorrhage, meningitis) disrupt the normal sympathetic stimulation of the kidneys which leads to suppression of the RAAS and decreased reabsorption of sodium along the nephron Euvolemic causes - total body water increases with stable total body sodium Syndrome of inappropriate ADH secretion (SIADH) SIADH is the most common cause of hyponatremia in hospitalized patients. In SIADH, inappropriate ADH secretion increases the absorption of free water at the renal collecting duct causing serum sodium concentrations to fall. Most patients with SIADH are euvolemic despite the increased reabsorption of free water. This occurs because intravascular volume expansion inhibits the RAAS and stimulates natriuretic peptides. A suppressed RAAS and the natriuretic effects of ANP and BNP help to reduce intravascular volume, but they also promote sodium excretion which can worsen SIADH. Because of this, SIADH is best treated with fluid restriction as opposed to normal saline because infused sodium is excreted at a greater rate than the infused water, and the net effect is the addition of more electrolyte-free water. Causes of SIADH include the following: Medications (see medications associated with SIADH below) CNS disorders (e.g. trauma, encephalitis, stroke, TIA, hydrocephalus) Ectopic production (e.g. small cell carcinoma of the lung, lymphoma) Pulmonary diseases (e.g. pneumonia, tuberculosis, bronchiectasis) HIV Other (e.g. pain, postsurgery, mechanical ventilation) Psychogenic polydipsia - drinking > 18 liters of water a day or > 750 ml/hour Potomania - excessive beer drinking which provides high amount of fluid and a relatively low amount of solutes Reset osmostat - condition seen in elderly patients and pregnancy where the brain regulates serum osmolality around a reduced set point. This condition differs from SIADH in that patients are able to dilute their urine in response to a water load. Severe hypothyroidism - mechanism is unclear but possibly due to reduced cardiac output and GFR Cortisol deficiency (e.g. Addison's disease) - cortisol inhibits ADH release. When it is deficient, ADH release is increased. Hypervolemic causes - total body water increases more than total body sodium. Water retention is driven by a decrease in effective circulating volume. Congestive heart failure Cirrhosis Renal failure (acute and chronic) Nephrotic syndrome Severe hypoproteinemia (albumin < 2 g/dl)
Isotonic hyponatremia (serum osmolality 275 - 290 mOsm/kg)
Pseudohyponatremia Under normal conditions, serum is composed of about 93% water. When levels of fats and proteins are significantly elevated, they can displace water from a serum sample so that the fraction of water may fall below 80%. The displaced water contains sodium, and when serum sodium concentrations are measured, they may come back spuriously low. If a lab uses direct ion-selective electrode measurement techniques, this phenomenon does not occur and the measured sodium will be correct. Causes of Pseudohyponatremia include the following: Hypertriglyceridemia Hypercholesterolemia Cholestasis Hypergammaglobulinemia (e.g. monoclonal gammopathy, multiple myeloma) IVIG administration Absorption of solutions used in procedures Solutions used for irrigation during urological (e.g. TURP) and gynecological procedures (e.g. hysteroscopy) can be absorbed. These solutions contain glycine, sorbitol, and mannitol which are nonionic solutes that pull free water into the serum through osmosis. The increase in serum water can lower sodium concentrations while osmolality remains normal or elevated. Sucrose and maltose in IVIG infusions Sucrose and maltose are present in some IVIG solutions. Sucrose and maltose are nonionic solutes that pull free water into the serum through osmosis. The increase in serum water can lower sodium concentrations while osmolality remains normal or elevated.
Hypertonic hyponatremia (serum osmolality > 290 mOsm/kg)
Overview Hypertonic hyponatremia occurs when the presence of osmotically active solutes in the serum pull free water into the serum through osmosis. Total body sodium levels are normal, but the shift of water into the serum lowers sodium concentrations and causes a "dilutional hyponatremia." Some examples of hypertonic hyponatremia are discussed below. Hyperglycemia Abnormally high glucose concentrations can cause hypertonic hyponatremia. The following correction factors can be used to estimate serum sodium concentrations if glucose levels were normal. Glucose 100 - 400 mg/dl - sodium levels drop 1.6 mEq/L for every 100 mg/dl increase in glucose above 100 mg/dl Glucose > 400 mg/dl - sodium levels drop 2.4 mEq/L for every 100 mg/dl increase in glucose above 400 mg/dl Mannitol Mannitol is given to patients with brain edema because it elevates plasma osmolality, but it does not cross the blood-brain barrier. The osmolality gradient it creates between the brain and the periphery causes fluid to shift from the brain to the periphery and dilutional hyponatremia may occur. Absorption of solutions used in procedures Solutions used for irrigation during urological (e.g. TURP) and gynecological procedures (e.g. hysteroscopy) can be absorbed. These solutions contain glycine, sorbitol, and mannitol which are nonionic solutes that pull free water into the serum through osmosis. The increase in serum water can lower sodium concentrations while osmolality remains normal or elevated. Sucrose and Maltose in IVIG infusions Sucrose and maltose are present in some IVIG solutions. Sucrose and maltose are nonionic solutes that pull free water into the serum through osmosis. The increase in serum water can lower sodium concentrations while osmolality remains normal or elevated.

• Medications that have been associated with SIADH
• Drugs that stimulate ADH release
• Amitriptyline (Elavil®)
• Carbamazepine (Tegretol®)
• Carboplatin
• Cisplatin
• Cotrimoxazole
• Cyclophosphamide
• Desipramine (Norpramin®)
• Haloperidol (Haldol®)
• Ifosfamide
• Levamisole
• MAO inhibitors
• MDMA "Ecstasy" "Molly" (3,4-methylenedioxymethamphetamine)
• Melphalan
• Methotrexate
• Nicotine
• Opiate medications
• Oxcarbazepine (Trileptal®)
• SSRI antidepressants
• Thioridazine (Mellaril®)
• Trifluoperazine (Stelazine®)
• Valproic acid (Depakote®)
• Vinblastine
• Vincristine
• Drugs that enhance the effects of ADH
• Carbamazepine (Tegretol®)
• Chlorpropamide
• Clofibrate
• Cyclophosphamide
• Desmopressin (DDAVP)
• Griseofulvin
• Lamotrigine (Lamictal®)
• NSAIDs
• Oxytocin
• Theophylline
• Tolbutamide
• Other drugs with unclear mechanism
• ACE inhibitors
• Bromocriptine
• Oxytocin
• Venlafaxine [2,19,20,22]

• Symptoms
• Symptoms of hyponatremia depend upon the degree and acuteness of the decline in sodium levels. Patients with sodium levels > 120 mEq/L typically have no symptoms. When levels fall below 120 mEq/L, nonspecific symptoms such as headache, fatigue, nausea, vomiting, and muscle cramps may occur. When hyponatremia becomes severe (< 115 mEq/L), the patient is at risk for brain edema and neurologic decline (e.g. obtundation, seizures, coma). Rapid declines (< 48 hours) in sodium levels are more likely to cause symptoms than gradual ones. [19,20]

• Reference [19,20]

Steps for evaluating hyponatremia
Step 1 - check serum osmolality If osmolality is high, consider causes of hypertonic hyponatremia If osmolality is normal, consider causes of isotonic hyponatremia If osmolality is low, then true hyponatremia exists. Consider causes of hypotonic hyponatremia and proceed to Step 2
Step 2 - check urine osmolality Urine osmolality < 100 mOsm/kg indicates proper renal response (dilute urine). Consider psychogenic polydipsia, reset osmostat, and malnutrition. Urine osmolality > 100 mOsm/kg indicates a high ADH state. Assess patient volume status and proceed to Step 3.
Step 3 - check a spot urine sodium and/or calculate the fractional excretion of sodium Fractional excretion of sodium is calculated with the following formula: Fractional excretion of sodium (FENa) = (UNa x PCr x 100) / (PNa x UCr) where UNa is urine sodium, PCr is plasma creatinine, PNa is plasma sodium, and UCr is urine creatinine Diuretics can increase FENa to > 20% so they must be discontinued for at least 24 hours before measuring Urine sodium < 10 mEq/L or FENa < 1% indicates proper renal response (increased sodium reabsorption). Consider extrarenal causes (e.g. diarrhea, vomiting, CHF, cirrhosis) Urine sodium > 20 mEq/L or FENa > 2% indicates renal sodium loss. Consider renal disease (e.g. nephropathy), diuretics, and SIADH Diagnostic criteria for SIADH Normal hepatic, renal, and cardiac function Normal thyroid and adrenal function Hypotonic hyponatremia Urine osmolality > 100 mOsm/kg (typically > 400 - 500 mOsm/kg)
Other tests that may be helpful in select patients TSH - severe hypothyroidism Cortisol - adrenal insufficiency Liver function tests - cirrhosis BNP - CHF Urine protein - nephropathy Chest imaging - ADH-secreting lung cancer; other lung disease Brain imaging - CNS disorders associated with SIADH Serum protein electrophoresis (SPEP) - monoclonal gammopathy Serum lipids - pseudohypokalemia Serum glucose - hyperglycemia HIV - cause of SIADH

• Treatment
• Significant hyponatremia can lead to life-threatening cerebral edema. In most tissues, sodium concentrations in plasma and interstitial fluid are equivalent because sodium passes freely between these compartments. In the brain, capillaries are lined by astrocyte foot processes which form the blood-brain barrier. The blood-brain barrier is impermeable to sodium which means that brain interstitial fluid is unable to rapidly adjust its osmolality in response to hyponatremia. When serum osmolality drops too quickly, osmosis pulls water into brain tissue and cerebral edema occurs.
• Treating significant hyponatremia is complicated, because rapid corrections of sodium levels can kill astrocytes and lead to osmotic demyelination syndrome (ODS). ODS is a permanent condition, and in severe cases, the patient is left in a vegetative state.
• The recommendations below provide some general guidance on treating hyponatremia. Patients with severe and/or symptomatic hyponatremia should be treated in the intensive care unit. [17,18]

• Hyponatremia levels and acuity
• Mild hyponatremia: 130 - 135 mEq/L
• Moderate hyponatremia: 125 - 129 mEq/L
• Severe hyponatremia: < 125 mEq/L
• Acute hyponatremia: < 48 hours
• Chronic hyponatremia: ≥ 48 hours or unknown

• Treatment recommendations for symptomatic hyponatremia
• Acute hyponatremia (< 48 hours)
• Patients with acute hyponatremia (< 48 hours) should have their sodium increased by 4 - 6 mEq/L as quickly as possible to prevent brain herniation
• For severe symptoms, give 100 mL of 3% saline infused intravenously over 10 minutes up to 3 times
• For mild to moderate symptoms and low risk for herniation, give 3% NaCl infused at 0.5 - 2 ml/kg/hr
• Chronic hyponatremia (≥ 48 hours or unknown)
• Correct sodium by 4 - 8 mEq/L per day
• Risk factors for ODS include hypokalemia, liver disease, malnutrition, and alcoholism
• For patients at high risk of ODS, correct sodium by 4 - 6 mEq/L per day and do not correct sodium by more than 8 mEq/L in any 24-hour period
• For patients at normal risk for ODS, the maximum correction is 10 - 12 mEq/L in any 24-hour period and 18 mEq/L in any 48-hour period
• The formula below can be used to estimate the change in sodium levels based on the selected infusate

• Calculating sodium replacement
• The amount of sodium infusate needed to raise the serum sodium by a desired level can be calculated with the formula below
• Change in serum Na⁺ (mEq/L) = [(Infusate Na⁺ + infusate K⁺) - serum Na⁺] / [Total body water + 1]
• Where the estimated total body water in liters is 0.6 L/kg in men and children, 0.50 L/kg in women and elderly men, and 0.45 L/kg in elderly women
• Infusate Na⁺ and infusate K⁺ are the number of mEq in one liter of the infusion
• 3% sodium chloride contains 513 mEq of Na⁺ per liter
• 0.9% sodium chloride contains 154 mEq of Na⁺ per liter
• Example:
• Patients is an 40 year old female that weighs 60 kg with symptomatic hyponatremia and a sodium of 112 mEq/L
• Provider would like to raise the patient's sodium by 3 mEq/L with an infusion of 3% NaCl
• Using the above formula, 1 liter of 3% NaCl would raise her sodium by 12.9 mEq/L.
• Change in Na⁺ = [(513 + 0) - 112 / [(0.5 X 60) + 1] = 12.9
• Given that 1 liter of 3% NaCl raises sodium by 12.9 mEq/L, 232 ml would raise sodium by 3 mEq/L (3/12.9 = 0.232 L)
• The provider orders a 232 ml infusion of 3% NaCl

• Treatment recommendations for SIADH
• In severe cases, fluid restriction with a goal of 500 ml/day below the 24-hour urine output is first-line therapy. If fluid restriction is not successful, consider demeclocycline (blocks effect of ADH in collecting duct), urea (produces osmotic diuresis), or vasopressin receptor antagonists (conivaptan, tolvaptan).
• Infused normal saline is not recommended because the infused sodium is excreted at a greater rate than the infused water and the net effect is the addition of more electrolyte-free water
• In asymptomatic patients, fluid restriction to < 1000 ml/day is recommended along with addressing the underlying cause if possible (e.g. medications). Loop diuretics (furosemide 20 - 40 mg/day) in combination with increased dietary sodium or 6 - 9 grams of sodium chloride tablets per day (each 1 gram sodium chloride tablet contains 17 mEq of sodium) may also be tried. Demeclocycline 600 - 1200 mg/day, vasopressin receptor antagonists (conivaptan, tolvaptan), and urea may be used in resistant cases, but only under close observation by providers who are familiar with their use. [19,20,21]

• Treatment recommendations for hypovolemic hyponatremia
• Give isotonic saline to correct the volume contraction and hold diuretics. Replace potassium if necessary. [19,20]

• Treatment recommendations for hypervolemic hyponatremia
• Treat hypervolemic hyponatremia with salt and fluid restriction, loop diuretics, and correction of the underlying condition [19,20]

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• HYPERNATREMIA

• Overview
• Hypernatremia is defined as a plasma sodium level > 145 mEq/L. Hypernatremia is primarily seen in infants and eldery patients because these populations are at risk for inadequate fluid intake. Infants with diarrhea often do not receive proper fluid replacement, and elderly patients can have dementia and other neurologic disorders which impair the thirst mechanism and/or the ability to obtain fluids. In the ICU setting, hypernatremia occurs in up to 26% of patients due to the frequent use of 0.9% NaCl for fluid replacement.
• Hypernatremia occurs when there is a deficit of total body water in relation to the amount of sodium present. The deficit of water can occur through three primary mechanisms: (1) free water loss (e.g. diabetes insipidus) or unreplaced loss (e.g. impaired thirst), (2) hypotonic fluid loss (e.g. gastroenteritis, nasogastric suctioning), (3) sodium gain (e.g. drinking sea water, hypertonic IV fluids). Most cases of hypernatremia are due to inadequate fluid replacement so patients are typically hypovolemic, but it can also occur in euvolemic (e.g. diabetes insipidus) and hypervolemic patients (e.g. renal failure).
• The table below groups causes of hypernatremia by the three main underlying etiologies [24,25,26]

• Reference [24,25,26]

Causes of hypernatremia
Free water loss or unreplaced loss Impaired thirst mechanism - may occur from lesions to the hypothalamus, granulomatous diseases, vascular abnormalities, and trauma Inadequate intake (e.g. altered mental status, infants) Central diabetes insipidus (DI) - central diabetes insipidus occurs when the brain does not secrete adequate amounts of ADH. Interestingly, most patients with DI and an intact thirst mechanism do not present with hypernatremia. This occurs because the thirst mechanism is so strong that patients with DI often consume enough water to offset the loss of up to 15 liters of free water a day. Central DI can occur secondary to the following conditions: Idiopathic Head trauma Cranial neoplasm (e.g. craniopharyngioma, pinealoma, meningioma, germinoma, lymphoma, metastatic disease) Pituitary damage (e.g. sarcoidosis, histiocytosis, surgery, trauma) Aneurysms - particularly anterior communicating Meningitis / Encephalitis Guillain–Barré syndrome Drugs (e.g. ethanol, phenytoin) Nephrogenic diabetes insipidus (DI) - nephrogenic DI occurs when the kidneys do not have an adequate response to ADH. Nephrogenic DI may be congenital or acquired, and it is a side effect of some medications. Interestingly, most patients with DI and an intact thirst mechanism do not present with hypernatremia. This occurs because the thirst mechanism is so strong that patients with DI often consume enough water to offset the loss of up to 15 liters of free water a day. Causes of acquired nephrogenic DI include the following: Intrinsic kidney disease (e.g. medullary cystic disease, polycystic kidney disease, nephrocalcinosis, Sjögren’s syndrome, lupus, papillary necrosis, sarcoidosis, sickle cell nephropathy) Obstructive kidney disease Hypercalcemia Hypokalemia Medications
Hypotonic fluid loss Renal loss Loop diuretics Osmotic diuresis (e.g. mannitol, hyperglycemia) Postobstructive diuresis Acute tubular necrosis Gastrointestinal loss Vomiting Diarrhea Nasogastric suctioning Enterocutaneous fistula Osmotic laxatives Cutaneous loss Burns Excessive sweating
Sodium gain Hypertonic fluids (e.g. sodium bicarbonate infusions, hypertonic saline) Ingestion of seawater - seawater is about 3 - 3.5% NaCl Sodium chloride tablets Hypertonic dialysis Hypertonic feeding preparations Hyperaldosteronism - promotes retention of sodium in the collecting duct Cushing's syndrome - excess corticosteroids have mineralocorticoid activity

• Medications that have been associated with nephrogenic diabetes insipidus
• Amphotericin B
• Cidofovir
• Cimetidine
• Clozapine
• Colchicine
• Contrast agents
• Cyclophosphamide
• Demeclocycline
• Dopamine
• Epirubicin
• Fluvoxamine
• Foscarnet
• Gentamicin
• Ifosfamide
• Lithium
• Methicillin
• Methoxyflurane
• Ofloxacin
• Orlistat
• Phenytoin (uncommon at therapeutic doses)
• Pimozide
• Propoxyphene
• Rifampin
• Streptozocin
• Vasopressin receptor antagonists (conivaptan, tolvaptan)
• Verapamil
• Vinblastine [2,24,26]

• Symptoms
• Most patients with hypernatremia are also hypovolemic so they often have symptoms of dehydration (e.g. hypotension, tachycardia). Patients with diabetes insipidus will have polyuria and polydipsia. Infants may display hyperpnea, weakness, restlessness, irritability, insomnia, and lethargy.
• Severe hypernatremia (> 160 mEq/L) and/or hypernatremia with an acute onset (< 24 hours) can cause brain shrinkage. In most tissues, sodium concentrations in plasma and interstitial fluid are equivalent because sodium passes freely between these compartments. In the brain, capillaries are lined by astrocyte foot processes which form the blood-brain barrier. The blood-brain barrier is impermeable to sodium which means that brain interstitial fluid is unable to rapidly adjust its osmolality in response to hypernatremia. When serum osmolality increases too quickly, osmosis pulls water out of the brain tissue and brain shrinkage occurs. Brain shrinkage can cause blood vessels to tear which can lead to hemorrhaging, neurologic damage, and even death.

• Diagnosis
• The etiology of hypernatremia can typically be determined by evaluating the patient's volume status and renal concentrating ability. Patients with diabetes insipidus often do not have hypernatremia but can develop it if access to water is limited. The labs below may be helpful depending on the patient presentation. [24,25,26]

• References [24,25,26,27]

Evaluating hypernatremia
Evaluating patient volume status Spot urine sodium - a spot urine sodium < 10 mEq/L suggests renal sodium retention secondary to intravascular volume contraction BUN to serum creatinine ratio - a BUN to serum creatinine ratio of > 20:1 usually indicates dehydration
Evaluating renal concentrating ability Urine osmolality Hypovolemic patients - urine osmolality > 600 mOsm/kg with a low spot urine sodium (< 10 mEq/L) indicates renal fluid retention and suggests an extrarenal source of water loss (e.g. gastrointestinal, dermal). Urine osmolality < 300 mOsm/kg with a high spot urine sodium (> 20 mEq/L) suggests renal fluid loss (e.g. diuretics, osmotic diuresis, intrinsic renal disease) Euvolemic patients - urine osmolality > 600 mOsm/kg indicates appropriate renal fluid retention and suggests decreased water intake or increased insensible losses. Urine osmolality < 300 mOsm/kg suggests diabetes insipidus.
Evaluating for diabetes insipidus Water deprivation test A water deprivation test can help differentiate central from nephrogenic DI. To perform the test, water is withheld from the patient and urine osmolality is checked hourly. Once the osmolality varies by less than 30 mOsm/kg on 2 sequential tests, the patient is given ADH. One hour later, the urine osmolality is rechecked. Results are interpreted as follows: Central DI - urine osmolality < 300 mOsm/kg after water deprivation and > 750 mOsm/kg after ADH administration Nephrogenic DI - urine osmolality < 300 mOsm/kg after water deprivation and there is no rise in urine osmolality after ADH administration Partial DI - urine osmolality of 300 - 750 mOsm/kg after water deprivation and < 750 mOsm/kg after ADH administration Primary polydipsia - urine osmolality > 750 mOsm/kg after water deprivation and < 750 mOsm/kg after ADH administration ADH (vasopressin) level - a low ADH level after water deprivation indicates central DI. A normal or high level after water deprivation suggests nephrogenic DI. Urine specific gravity - urine specific gravity is < 1.005 in DI

• Treatment
• The treatment of hypernatremia depends upon the acuity of the condition and the underlying etiology. Treating significant hypernatremia is complicated because rapidly lowering the serum sodium level can cause permanent neurological damage. Sodium does not diffuse freely across the blood-brain barrier which means that brain tissue cannot adapt quickly to changes in serum osmolality. Sudden drops in serum osmolality can cause water to enter the brain tissue through osmosis and brain swelling ensues. The recommendations below provide some general guidance on treating hypernatremia. [24,26]

• Symptomatic hypernatremia treatment recommendations
• Acute symptomatic hypernatremia (< 24 hours)
• Hypernatremia that occurs in less than 24 hours (e.g. inadvertent administration of hypertonic fluids) puts the patient at risk for brain shrinkage and vessel rupture. This type of hypernatremia can be corrected more rapidly because the brain has not had adequate time to raise its osmolality.
• The recommended rate of sodium reduction in acute hyponatremia is 1 mEq/L per hour. Some sources recommend a reduction of 2 - 3 mEq/L per hour over 2 - 3 hours while not exceeding 12 mEq/L in 24 hours. [24,26]
• Chronic hypernatremia (> 24 hours or unknown)
• In chronic hypernatremia, brain tissue has adapted to the increase in serum osmolality so sodium levels should be corrected at a slower pace
• The recommended rate of sodium reduction in chronic hypernatremia is 0.5 mEq/L per hour with a target reduction of 8 - 10 mEq/L over 24 hours [24,26]

• Calculating free water replacement
• The amount of free water needed to lower the serum sodium by a desired level can be calculated with the formula below
• Change in serum Na⁺ (mEq/L) = [(Infusate Na⁺ + infusate K⁺) - serum Na⁺] / [Total body water + 1]
• Where the estimated total body water in liters is 0.6 L/kg in men and children, 0.50 L/kg in women and elderly men, and 0.45 L/kg in elderly women
• Infusate Na⁺ and infusate K⁺ are the number of mEq in one liter of the infusion
• 5% dextrose in water (D5W) contains no sodium
• 0.2% sodium chloride in D5W contains 34 mEq of Na⁺ per liter
• 0.45% sodium chloride contains 77 mEq of Na⁺ per liter
• Ringer's lactate contains 130 mEq of Na⁺ per liter
• 0.9% sodium chloride contains 154 mEq of Na⁺ per liter [24]
• Example:
• Patients is an 50 year old female who weighs 53 kg with a sodium of 159 mEq/L
• Provider would like to lower the patient's sodium by 6 mEq/L over the next 12 hours with an infusion of 0.45% NaCl
• Using the above formula, 1 liter of 0.45% NaCl would lower her sodium by 2.98 mEq/L
• Change in Na⁺ = [(77 + 0) - 159 / [(0.5 X 53) + 1] = -2.98
• Given that 1 liter of 0.45% NaCl lowers sodium by about 3 mEq/L, 2 liters would lower sodium levels by 6 mEq/L
• The provider orders a 0.45% NaCl infusion at a rate of 167 ml/hr over the next 12 hours

• Diabetes insipidus treatment
• For central DI, desmopressin (DDAVP), a synthetic analog of ADH, is recommended. Desmopressin comes in tablet and nasal spray forms. Adult dosing for the tablet form typically starts at 0.05 mg twice daily. It is titrated based on response to a daily dose of 0.1 - 1.2 mg given in 2 - 3 divided doses. In trials, most patients were maintained on doses in the range of 0.1 - 0.8 mg/day. Adult dosing for DDAVP nasal spray is typically in the range of 0.1 - 0.4 ml per day given in 1 - 3 divided doses. Most adults can be maintained on 0.1 ml twice daily. [DDAVP tablet PI] [DDAVP nasal spray PI]
• Nephrogenic DI is more difficult to treat because giving synthetic ADH does not help. Certain medications from different drug classes can help to abate water loss mostly by reducing the delivery of sodium and water to the distal nephron. Thiazide diuretics and amiloride promote sodium loss in the distal nephron. This in turn stimulates sodium and fluid reabsorption in the proximal nephron and the net effect is decreased delivery of water and solutes to the collecting duct. NSAIDs have a similar effect through their inhibition of the RAAS, and a low sodium diet can enhance these processes. The sulfonylurea chlorpropamide has been shown to enhance the renal response to ADH. Any medication that may be contributing to the issue should be discontinued (see nephrogenic DI meds). [26,27]

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• CHLORIDE

• Overview
• Chloride is the main extracellular anion, and together with bicarbonate, it helps to maintain electroneutrality with the predominant cation, sodium. Chloride and bicarbonate levels often move in opposite directions because they replace each other when the other is lost so that electroneutrality is preserved in the extracellular space. Because of this association with bicarbonate, chloride levels are affected by acid-base disorders. Unlike sodium and potassium, the body does not directly regulate chloride levels. Rather, it indirectly controls them through the regulation of sodium and bicarbonate. Chloride conservation and elimination primarily takes place in the kidneys. After filtration into the nephron, 65 - 70% of chloride is passively reabsorbed in the proximal tubule, 25% is actively reabsorbed in the Loop of Henle, and the remainder is reabsorbed in the distal tubule. Chloride typically follows sodium and water along the nephron, but acid-base disorders that affect the excretion of bicarbonate can modify its handling. [2,3,4]

• Hypochloremia
• Hypochloremia in adults is defined as a chloride level < 98 mEq/L. Hypochloremia may occur through excessive chloride loss, acid-base disorders, or extracellular fluid expansion. The correction of hypochloremia is primarily achieved by treating the underlying disorder. If chloride replenishment is necessary, it can be achieved with one of its salt forms, typically sodium chloride or potassium chloride. The choice of salt will depend upon the underlying disorder.
• Some causes of hypochloremia are listed below
• Excessive chloride loss
• Vomiting - gastric fluid contains 1.5 - 3 times more chloride than sodium
• Nasogastric suctioning
• Diarrhea
• Excessive sweating
• Diuretics - through direct chloride loss and metabolic alkalosis
• Intrinsic kidney disease (e.g. salt-losing nephropathy)
• Hyperaldosteronism - aldosterone stimulates bicarbonate retention in the distal nephron and chloride is lost
• Cushing's syndrome - through excessive mineralocorticoid activity
• Corticosteroids - through excessive mineralocorticoid activity
• Bartter and Gitelman syndrome - rare disorders that decrease the function of the Na-Cl transporter in the distal nephron
• Acid-base disorders
• Metabolic alkalosis - metabolic alkalosis is typically driven by chloride loss and/or excessive mineralocorticoid activity
• Diuretics - through direct chloride loss and metabolic alkalosis
• Chronic respiratory acidosis - promotes the retention of bicarbonate in the kidneys and chloride is lost
• High anion gap acidosis - bicarbonate retention in the kidneys causes chloride loss and excessive anion displaces chloride in the extracellular fluid
• Extracellular fluid expansion
• Primary polydipsia
• SIADH
• Hypotonic fluid infusion (e.g. D5W) [2,3,4]

• Hyperchloremia
• Hyperchloremia in adults is defined as a chloride level > 110 mEq/L. Hyperchloremia may occur through excessive chloride gain, decreased chloride excretion, acid-base disorders, and extracellular fluid contraction. The correction of hyperchloremia is achieved by treating the underlying disorder.
• Some causes of hyperchloremia are listed below
• Excessive chloride gain
• Hypertonic saline fluids (e.g. 3% NaCl, swallowing seawater)
• Excessive normal saline
• Normal saline with KCl
• Total parenteral nutrition
• Decreased chloride excretion
• Kidney failure
• Renal tubular acidosis
• Nephrotic syndrome
• Acid-base disorders
• Normal anion gap metabolic acidosis - bicarbonate loss causes chloride retention
• Respiratory alkalosis - excessive CO₂ loss causes bicarbonate excretion and chloride retention
• Extracellular volume contraction
• Dehydration
• Diabetes insipidus [2,3,4]

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• CALCIUM AND PHOSPHORUS HOMEOSTASIS

• Overview
• Calcium and phosphorus (also called phosphate) are closely related, and they are regulated by the same hormones, mainly parathyroid hormone and calcitriol (1,25 dihydroxyvitamin D)
• The human body contains about 1000 grams of calcium and 99% of it is found in bones. While most calcium is utilized to harden bones, the remaining 1% plays an important role in muscle contraction, nerve conduction, and blood clotting (calcium is factor IV in the coagulation cascade). Low calcium levels increase the excitability of neurons and can lead to tetany (sustained muscle contractions). High calcium levels depress nerve activity and can lead to lethargy, constipation, and weakness.
• The human body contains about 1000 grams of phosphorus and 85% of it is found in bones where it combines with calcium to form hydroxyapatite, a mineral that provides strength. The remaining 15% is found mostly in cells where it serves as a major intracellular anion. Intracellular phosphorus is involved in a number of important physiologic processes including the metabolism of proteins, lipids, and carbohydrates, and the formation of high-energy bonds in ATP. It also acts as an acid-base buffer and is part of a number of cellular components including phospholipid membranes, RNA, DNA, and messenger proteins. [2,3,4,34]

• Calcium and phosphorus regulation
• Calcium
• Because of its role in nerve conduction and muscle contraction, calcium levels must be tightly regulated. The main hormones that control calcium levels are parathyroid hormone (PTH) and calcitriol. Calcitonin plays a role too, but in adults, its actions have a minimal effect; even after thyroidectomy when calcitonin levels are unmeasurable, calcium regulation remains intact.
• PTH regulates calcium levels through a number of mechanisms. When calcium levels are low, PTH is released from the parathyroid glands. PTH stimulates bone resorption which causes the release of calcium and phosphorus from bones. In the kidneys, it promotes the reabsorption of calcium and the excretion of phosphorus. It also stimulates the conversion of calcidiol to its active form, calcitriol. Calcitriol enhances bone resorption, and it stimulates the uptake of calcium and phosphorus from the small intestine. When calcium levels are high, PTH release is inhibited and these processes are suppressed.
• In plasma, about 50% of calcium circulates in its ionized (free) form which is also its active form. Ten percent is complexed with anions, and the remaining 40% is bound to protein, mainly albumin. If albumin levels are low, total calcium levels will not reflect the true amount of ionized calcium. In these cases, ionized calcium levels can be measured directly. Another widely used method for estimating the correct calcium level is with the formula below:
• Corrected calcium (mg/dL) = measured total Ca (mg/dL) + 0.8 (4.0 - serum albumin [g/dL])
• where 4 represents the normal albumin level
• Acid-base disorders can also affect calcium protein binding; alkalosis increases binding and acidosis decreases it [2,3,4,32,34]

• Phosphorus
• Phosphorus and calcium regulation are closely related. In bones, phosphorus combines with calcium to form hydroxyapatite, the mineral that provides strength. In extracellular fluid, chemical inhibitors prevent calcium and phosphorus from binding with each other. If phosphorus levels get too high (e.g. kidney disease), the inhibitors can become overwhelmed and calcium phosphate starts to precipitate in soft tissues. This can lead to cardiac and respiratory failure. Conversely, if phosphate levels get too low, bone mineralization is impaired and osteomalacia can occur.
• High serum phosphorus levels can bind calcium and lower the amount of ionized calcium. This in turn stimulates PTH release. While PTH can stimulate processes that increase phosphorus levels (e.g. bone resorption, calcitriol production), these effects are overcome by its ability to enhance phosphorus excretion in the kidneys. In addition, high phosphorus levels directly inhibit the conversion of calcidiol to calcitriol. The net effect of these processes is lowering of phosphorus levels. When phosphorus levels are low, these processes are suppressed. [2,3,4]

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• HYPOCALCEMIA

• Overview
• The lower limit of normal for serum calcium levels varies by lab, but in general, hypocalcemia in adults is defined as a total calcium level < 8.8 mg/dl (ionized calcium < 4.7 mg/dl). The incidence of hypocalcemia in the general population is not well-defined. The most common causes of hypocalcemia are acute and chronic renal failure followed by vitamin D deficiency, magnesium deficiency, and acute pancreatitis. Transient hypocalcemia is seen in about 30% of patients after thyroidectomy or parathyroid surgery while permanent hypocalcemia is much less frequent (1 - 2%). [32,34,35]

• References [32,34,35]

Causes of hypocalcemia

Kidney disease Hypocalcemia in kidney disease typically occurs when the GFR falls below 30 ml/min. It is primarily driven by 2 processes: (1) decreased renal conversion of calcidiol to calcitriol, (2) decreased renal excretion of phosphate. Loss of calcitriol decreases calcium absorption in the intestines, and rising serum phosphate levels bind ionized calcium and render it inactive. Reduced ionized calcium levels stimulate PTH production and bone resorption is increased. The end result is bone resorption that outpaces bone formation causing weakened bones and an increased risk of fractures. Another possible adverse effect is an increased risk of cardiovascular disease from calcium phosphate deposition in the vasculature. Vitamin D deficiency - vitamin D deficiency leads to decreased calcium absorption in the intestines. Vitamin D deficiency may occur from inadequate intake or malabsorption (e.g. celiac disease, shortened bowel, Crohn's disease) Hypomagnesemia - severe hypomagnesemia (< 1 mg/dl) can affect the release of PTH from the parathyroid gland and lead to hypocalcemia Acute pancreatitis - the exact cause of hypocalcemia in pancreatitis is unknown but may involve the following: (1) generation of free fatty acids that bind calcium salts in the pancreas, (2) release of lipase that degrades omental fat causing calcium binding in the peritoneum, (3) hypoparathyroidism, (4) hypomagnesemia Hypoparathyroidism Hypoparathyroidism can be hereditary or acquired. Hereditary hypoparathyroid syndromes are rare. Acquired hypoparathyroidism is more common and may be caused by the following: Neck irradiation Radioiodine therapy for Graves' disease Parathyroid surgery (transient hypocalcemia - 33% | permanent hypocalcemia - 2%) Thyroidectomy (transient hypocalcemia - 27% | permanent hypocalcemia - 1%) Infiltrative diseases of the thyroid (e.g. hemochromatosis, granulomatous, metastatic) Autoimmune destruction (e.g. polyglandular autoimmune disease) Pseudohypoparathyroidism - pseudohypoparathyroidism occurs when PTH receptors are resistant to the effects of PTH. Receptor defects are inherited, and these syndromes are rare. Liver disease - vitamin D2 and D3 are converted in the liver to calcidiol. Significant liver disease can impair this process. See vitamin D metabolism. Hungry bone syndrome - after surgical correction of hyperparathyroidism, a sudden decrease in PTH levels can cause bones to undergo rapid remodeling. These "hungry" bones take up lots of calcium which can lead to hypocalcemia. Sepsis - hypocalcemia is sometimes seen in severe sepsis. The mechanism is not completely understood, but may be related to impaired PTH secretion, decreased calcitriol production, and/or hypomagnesemia. Hyperphosphatemia - phosphorus binds calcium and lowers its active levels. Hyperphosphatemia can occur from decreased excretion (kidney disease) and in conditions where there is a sudden release of phosphorus from cells (e.g. tumor lysis syndrome, rhabdomyolysis). Pseudohypocalcemia - gadolinium-based contrast agents (e.g. gadodiamide, gadoversetamide) used in MRI scans can interfere with calcium assays and cause false-low readings. This usually occurs if a calcium level is drawn within 24 hours of the agent being given. Medications (see below)

• Medications that have been associated with hypocalcemia
• Bisphosphonates (e.g. Fosamax, Actonel)
• Calcitonin
• Carbamazepine - carbamazepine is a CYP inducer and it may increase vitamin D metabolism
• Cinacalcet - cinacalcet is a calcimimetic agent used to treat secondary hyperparathyroidism in dialysis patients
• Cisplatin - causes hypomagnesemia
• Citrated blood or plasma products - citrate binds calcium. May occur in patients with hepatic or renal failure who are slow to clear citrate.
• Denosumab (Prolia®)
• Estrogens - estrogens inhibit bone resorption and may worsen hypocalcemia
• Ethanol - inhibits PTH release
• Ethylenediaminetetraacetic acid (EDTA) - chelating agent
• Fluoride
• Foscarnet
• Gadolinium-based contrast agents (e.g. gadodiamide, gadoversetamide) - interfere with calcium assays and can cause false-low readings
• H-2 blockers (e.g. famotidine) - suppressed gastric acid production may reduce calcium and magnesium absorption
• Leucovorin
• Nivolumab
• Pembrolizumab
• Phenobarbital - phenobarbital is a CYP inducer and it may increase vitamin D metabolism
• Phenytoin - phenytoin is a CYP inducer and it may increase vitamin D metabolism
• Proton pump inhibitors (e.g. omeprazole) - suppressed gastric acid production may reduce calcium and magnesium absorption
• Sodium phosphate products (Fleet® enema) - may cause hyperphosphatemia in susceptible populations (e.g. renal or hepatic failure, CHF)
• 5-fluorouracil [32,34,35]

• Symptoms
• Symptoms of hypocalcemia depend upon the magnitude of the deficit. Mild hypocalcemia is typically asymptomatic and often only discovered incidentally on routine labs. Low calcium levels increase the excitability of neurons and this can manifest as paresthesias, muscle cramps, tetany, and in severe cases, seizures. Cardiac changes including reduced contractility and prolonged QT interval can also occur. Two classic physical exam findings, Chvostek's sign and Trousseau's sign, are associated with hypocalcemia. Chvostek's sign is a facial twitch elicited by tapping on the facial nerve just below the zygomatic bone with the patient’s mouth slightly open. Trousseau's sign is elicited by inflating a blood pressure cuff to 20 mmHg above systolic blood pressure for 3 - 5 minutes. This occludes the brachial artery and the neuromuscular irritability induced by hypocalcemia causes wrist and metacarpophalangeal flexion, interphalangeal joint extension, and thumb adduction (see Trousseau's sign illustration). [32,34,35]

• References [2,32,34,35]

Steps for evaluating hypocalcemia
Step 1 - Confirm that hypocalcemia is real In plasma, about 50% of calcium circulates in its ionized (free) form which is also its active form. Ten percent is complexed with anions, and the remaining 40% is bound to protein, mainly albumin. If albumin levels are low, total calcium levels will not reflect the true amount of ionized calcium. In these cases, ionized calcium levels can be measured directly. Another widely used method for estimating the correct calcium level is with the formula below: Corrected calcium (mg/dL) = measured total Ca (mg/dL) + 0.8 (4.0 - serum albumin [g/dL]) where 4 represents the normal albumin level
Step 2 - Depending on the patient, consider the following Medications associated with hypocalcemia Serum creatinine and GFR - to look for kidney disease 25-hydroxy vitamin D (calcidiol) and 1,25-dihydroxy vitamin D (calcitriol) Reduced 25-hydroxy vitamin D suggests dietary deficiency, lack of sunlight, or malabsorption Reduced 1,25-dihydroxy vitamin D suggests kidney disease (see vitamin D metabolism) Magnesium level - to look for hypomagnesemia PTH level - low levels are seen in hypoparathyroidism and severe hypomagnesemia Phosphorus level Hyperphosphatemia is seen in kidney disease, tumor lysis syndrome, rhabdomyolysis, hypoparathyroidism and pseudohypoparathyroidism Hypophosphatemia is seen in vitamin D deficiency and hungry bone syndrome Amylase and lipase - if pancreatitis is suspected Liver function tests - to look for liver disease

• Treatment
• The treatment of hypocalcemia is focused on correcting the underlying disorder when possible. Treatments used in select etiologies are reviewed below.

• Severe hypocalcemia (< 7.5 mg/dl)
• Severe, symptomatic hypocalcemia requires prompt treatment. Most patients are treated with calcium gluconate (10 ml of 10% solution contains 94 mg of elemental calcium) which can be given as an initial bolus (100 - 300 mg over 5 - 10 minutes) followed by a slow infusion. Calcium chloride (10 ml of 10% solution contains 272 mg of elemental calcium) contains more calcium, but it must be given through a central line. After an initial bolus, calcium can be infused at a rate 0.5 mg/kg/hr and increased to 2 mg/kg/hr as needed. Patients on calcium infusions should be monitored closely under telemetry. [32,34,35]

• Chronic kidney disease
• Recommendations for monitoring and treating hypocalcemia and hyperparathyroidism from the National Kidney Foundation are presented below
• Monitoring
• CrCl 15 - 29 ml/min: check serum calcium and phosphate every 3 – 6 months, and PTH every 6 – 12 months
• CrCl < 15 ml/min: check serum calcium and phosphate every 1 - 3 months, and PTH every 3 - 6 months
• In both groups, check 25-hydroxy vitamin D level to screen for deficiency. Consider BMD in high-risk groups.
• Bone-specific alkaline phosphatase can also be used to evaluate for bone disease [36]

• Hyperphosphatemia treatment
• The 2017 NKF guidelines state that decisions about phosphate-lowering treatment should be based on progressively or persistently elevated serum phosphate and not on one reading. The goal of phosphate-lowering therapy is to lower phosphate levels toward the normal range. Phosphate-lowering therapies are reviewed below. The NKF guidelines do not make specific recommendations in regards to when therapies should be initiated or which therapies are preferred. [36]

• Low-phosphate diet - all patients with hyperphosphatemia should consume a low phosphate diet. The typical Western diet contains 1000 - 1200 mg of phosphorus a day. Restricting phosphorus intake to < 800 mg a day can help to lower phosphorus levels. Information on phosphate-restricted diets is available at the links below.
• PDF handout on reducing dietary phosphate
• NKF webpage on dietary phosphorus

• Calcium carbonate (Tums®, Os-Cal®, Caltrate®) calcium binds phosphate in the intestine and prevents its absorption. Calcium carbonate contains 40% elemental calcium, so 500 mg of calcium carbonate will have 200 mg of elemental calcium (0.40 X 500 mg). A typical starting dose for hyperphosphatemia is 200 mg of elemental calcium (500 mg calcium carbonate) with each meal. Calcium carbonate doses should not exceed 3750 mg/day (1500 mg elemental calcium) so that total daily calcium intake does not exceed 2000 mg. With calcium carbonate therapy, serum phosphorus levels decline by 0.9 mg/dl on average and calcium levels increase by 0.5 mg/dl on average. Calcium carbonate is inexpensive and has been used for many years. The main disadvantage is the increased risk of hypercalcemia.

• Calcium acetate (PhosLo®, Eliphos®) calcium binds phosphate in the intestine and prevents its absorption. Calcium acetate is available by prescription in 667 mg tablets and capsules. Each capsule contains 169 mg of elemental calcium. The recommended starting dose is 2 pills with each meal. Calcium acetate doses of 9 capsules/day provide 1521 mg of elemental calcium. Doses above this should be used with caution. Calcium acetate is more expensive than calcium carbonate but cheaper than other therapies. In a study from the PhosLo PI, an average of 3.4 tablets of calcium acetate per meal lowered phosphorus levels by 2.4 ml/dl over 12 weeks while calcium levels increased by 0.8 mg/dl over the same period. [PhosLo PI]

• Sevelamer (Renagel®, Renvela®) - sevelamer is an anion exchange resin that binds phosphorus in the intestine and prevents its absorption. Renagel is sevelamer hydrochloride and Renvela is sevelamer carbonate. Sevelamer carbonate was developed over concerns that the hydrochloride version could contribute to metabolic acidosis. Sevelamer is started at a dose of 800 mg (phosphorus 5.5 - 7.4 mg/dl) to 1600 mg (phosphorus ≥ 7.5 mg/dl) 3 times a day followed by titration to desired effect. In studies, sevelamer has been shown to reduce the average phosphorus level by 2 mg/dl over 52 weeks. The main advantage of sevelamer is that it does not raise calcium levels. The main disadvantages are gastrointestinal side effects and higher cost. [Renvela PI]

• Lanthanum (Fosrenol®) - lanthanum binds phosphorus in the intestines and prevents its absorption. Lanthanum comes in a chewable tablet in doses of 500, 750, and 1000 mg. The recommended starting dose is 500 mg three times a day with meals followed by titration to desired effect. In one trial, lanthanum (2250 mg/day) reduced phosphate levels by 2 mg/dl over 6 weeks. The main advantage of lanthanum is that it does not raise calcium levels. The main disadvantage is its high cost. [Fosrenol PI]

• Sucroferric oxyhydroxide (Velphoro®) - sucroferric oxyhydroxide is an iron-based phosphorus binder that binds phosphorus in the intestines and prevents its absorption. Sucroferric oxyhydroxide comes in 500 mg chewable tablets. The recommended starting dose is 500 mg three times a day with meals followed by titration to desired effect. In one trial, Velphoro reduced phosphorus levels by an average of 2.2 mg/dl over 12 weeks. [PMID 24646861] Velphoro is expensive and each tablet contains 500 mg of iron so it cannot be used in patients with iron overload disorders (e.g. hemochromatosis). [Velphoro PI]

• Ferric citrate (Auryxia®) - ferric citrate is an iron-based phosphorus binder that binds phosphorus in the intestines and prevents its absorption. Ferric citrate comes in a 210 mg tablet. The recommended starting dose is 2 tablets three times a day with meals. The dose can be titrated by 1 - 2 tablets a day at a minimum of 1 week intervals to a maximum of 12 tablets/day. In a trial from the Auryxia PI, Auryxia reduced serum phosphorus levels by about 2 mg/dl over a 52-week period. Auryxia has 210 mg of ferric iron in each tablet, and it is also approved to treat anemia in CKD. Auryxia has no generic and is very expensive. [Auryxia PI] [36,37]

• Hyperparathyroidism treatment
• The 2017 NKF guidelines state that the optimal PTH level in adult patients with kidney disease who are not on dialysis is unknown. Patients with progressively rising or persistently elevated PTH levels should be evaluated for hyperphosphatemia, hypocalcemia, high phosphate intake, and vitamin D deficiency. Adult patients with kidney disease who are not on dialysis should not routinely receive calcitriol or other vitamin D analogs. Calcitriol and vitamin D analogs may be reasonable in patients with severe and progressive hyperparathyroidism.
• Calcitriol and two other active vitamin D analogs are available by prescription. These drugs differ from dietary vitamin D supplements (ergocalciferol and cholecalciferol) in that they do not require kidney metabolism to become active. A brief review of each drug is provided below. It is important that patients maintain adequate calcium intake while taking these drugs; depending on the individual, combined dietary and supplemental calcium intake should range between 600 - 1200 mg/day. Frequent lab monitoring is required to prevent hypercalcemia. See vitamin D supplements and calcium supplements for more information on available supplement products. [36]

• Calcitriol (Rocaltrol®; 1,25 dihydroxyvitamin D) - calcitriol is the biologically active form of vitamin D (see vitamin D metabolism). The recommended starting dose of calcitriol in predialysis patients is 0.25 mcg/day. It may be increased to 0.5 mcg/day if necessary. [Rocaltrol PI]

• Doxercalciferol (Hectorol®) - doxercalciferol is a synthetic vitamin D2 analog. Doxercalciferol is converted in the liver to 1α,25-(OH)2D2, an active metabolite that does not require kidney metabolism. The recommended starting dose in predialysis patients is 1 mcg once daily. The dose may be increased by 0.5 mcg/day at 2-week intervals to a maximum of 3.5 mcg once daily. [Hectorol PI]

• Paricalcitol (Zemplar®) - paricalcitol is a synthetic version of calcitriol. It does not require metabolism to become active. The recommended starting dose in predialysis patients with a GFR of 15 - 60 ml/min is 1 mcg once daily if the PTH level is < 500 pg/ml and 2 mcg once daily if the PTH is > 500 pg/ml. The dose can then be adjusted based on follow-up PTH levels. [Zemplar PI]

• Hypoparathyroidism
• Post thyroidectomy and parathyroidectomy
• Transient hypocalcemia is common after thyroidectomy and parathyroid surgery. Severe cases may require parenteral calcium, but most cases can be managed with oral calcium and vitamin D. Most surgeons have a calcium supplement protocol that they follow starting on the day of surgery. A typical protocol may call for 200 - 600 mg of elemental calcium per day that is tapered down over 2 - 3 weeks to a maintenance dose of 100 - 200 mg/day. Calcium carbonate relies on stomach acid for absorption so its absorption is increased when taken with food; calcium citrate absorption is unaffected by food. A vitamin D supplement should be included to ensure a daily vitamin D intake of at least 600 IU/day. A paper that outlines one such protocol is available here - PMID 20610248.
• In resistant cases, calcitriol may be necessary. The recommended starting dose in hypoparathyroidism is 0.25 mcg/day titrated every 2 - 4 weeks to a maximum of 2 mcg/day with frequent monitoring of calcium levels. [35,38]

• Other causes
• Patients with hypoparathyroidism from other causes (e.g. idiopathic, autoimmune) are generally treated with calcium and vitamin D supplements. If these treatments are not adequate, a recombinant version of parathyroid hormone called Natpara® is available. Natpara® is given as a once daily subcutaneous injection. Natpara has been shown to increase the risk of osteosarcoma in rats, and therefore, its use should be reserved for patients who do not respond to other treatments. [Natpara PI] [35]

• Hypomagnesemia
• See hypomagnesemia below

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• HYPERCALCEMIA

• Overview
• The upper limit of normal for serum calcium levels varies by lab, but in general, hypercalcemia in adults is defined as a total calcium level > 10.4 mg/dl (ionized calcium > 5.9 mg/dl). The incidence of hypercalcemia in the general population is about 1 - 2%. Hyperparathyroidism and malignancy account for up to 90% of the cases. Causes of hypercalcemia can generally be broken down into PTH disorders, bone disorders, vitamin D disorders, and other causes. [28,32,33]

• References [28,29,30,31,32,33]

Causes of hypercalcemia
PTH disorders Primary hyperparathyroidism Primary hyperparathyroidism is the most common cause of hypercalcemia accounting for > 50% of cases. Hyperactive benign adenomas are the most common reason. Multiple endocrine neoplasia type 1 (MEN1) is an rare inherited disorder that can cause primary hyperparathyroidism Malignancy Malignancy is the second most common cause of hypercalcemia accounting for 33 - 50% of cases Hypercalcemia secondary to malignancy may result from direct osteolytic bone destruction (20% of cases), but more often, it occurs secondary to tumors that produce PTH-related peptide, a protein that mimics the activity of PTH (80% of cases). Other malignant causes that are very rare include vitamin D-secreting lymphomas and ectopic PTH secretion. Hypercalcemia secondary to PTH-related peptide is most commonly seen in squamous cell carcinomas of the head and neck, multiple myeloma, lymphomas, and cancers of the breast, kidney, lung, ovary, bladder, and prostate. Familial hypocalciuric hypercalcemia (FHH) Familial hypocalciuric hypercalcemia is a rare disorder caused by inherited (autosomal dominant) mutations in the calcium-sensing receptors that are found in the parathyroid glands and kidneys. The mutations decrease the calcium-sensing ability of the receptors, and the parathyroid gland does not respond appropriately to calcium levels. Patients with FHH typically have mild asymptomatic hypercalcemia with normal or slightly elevated PTH levels. A severe form of the disease called "neonatal severe hyperparathyroidism" can present right after birth with extreme hypercalcemia, respiratory distress due to hypotonia, fractures, and bone mineralization deficiencies. After excluding more common causes of hypercalcemia, FHH can be diagnosed with a 24-hour urine test. In FHH, urinary calcium excretion is < 100 mg/24 hours, and the calcium-creatinine excretion ratio (see formula below) is < 0.020. Genetic testing for calcium-sensing receptor (CaSR) mutations is also available. In most cases, FHH is considered a benign disease and treatment is not indicated. In rare cases, patients may develop pancreatitis that requires parathyroidectomy. Calcium-creatinine excretion ratio = [UCa × SCr] / [SCa × UCr], where UCa is the urinary calcium concentration, SCr is the serum creatinine, SCa is the serum calcium concentration, and UCr is the urinary creatinine concentration, all in mg/dl PTH analogs (Abaloparatide, Teriparatide) - PTH analogs used to treat osteoporosis may cause hypercalcemia Lithium - lithium can inhibit the PTH-suppressing effects of calcium on the parathyroid gland, and it can increase calcium reabsorption in the kidneys Renal transplant - patients with hyperparathyroidism from renal failure can develop hypercalcemia after they receive a renal transplant
Bone disorders Malignancy Malignancy is the second most common cause of hypercalcemia accounting for 33 - 50% of cases Hypercalcemia secondary to malignancy may result from direct osteolytic bone destruction (20% of cases), but more often, it occurs secondary to tumors that produce PTH-related peptide, a protein that mimics the activity of PTH (80% of cases). Other malignant causes that are very rare include vitamin D-secreting lymphomas and ectopic PTH secretion. Cancers that are often associated with osteolytic bone lesions include multiple myelomas, leukemia, and breast cancer Hyperthyroidism - excess thyroid hormone can stimulate osteoclastic bone resorption and lead to hypercalcemia Paget's disease - rare disorder that causes abnormal bone remodeling
Vitamin D disorders Excessive vitamin D intake Granulomatous diseases - granuloma macrophages possess an enzyme (25-hydroxyvitamin D–1α-hydroxylase) that converts calcidiol to its more active form, calcitriol. This can lead to increased calcium absorption and hypercalcemia. Granulomatous diseases include the following: Sarcoidosis Tuberculosis Fungal infections Leprosy
Other Thiazide diuretics - increase renal calcium reabsorption Calcium-containing antacids - consuming large amounts of calcium-containing antacids (calcium carbonate) can lead to the "milk-alkali syndrome." Milk-alkali syndrome is marked by hypercalcemia, metabolic alkalosis, and renal failure. Prolonged immobilization - prolonged immobilization can cause increased bone resorption, especially in person's with Paget's disease Hypervitaminosis A - probably through stimulation of osteoclasts Adrenal insufficiency - possibly through increased calcium reabsorption in the kidneys Hypophosphatasia - hypophosphatasia is a rare genetic disorder that is marked by defects in the tissue-nonspecific alkaline phosphatase (TNSALP) enzyme. TNSALP is involved in bone and tooth mineralization, and affected individuals have weakened bones, skeletal abnormalities, and hypercalcemia. Subcutaneous fat necrosis

• References [28,33]

Hypercalcemia levels
Degree	Total calcium (mg/dl)	Ionized calcium (mg/dl)
Mild	10.5 - 11.9	5.6 - 7.9
Moderate	12 - 13.9	8 - 9.9
Severe	≥ 14	≥ 10

• Symptoms
• Symptoms of hypercalcemia depend upon the degree of elevation and the acuity of onset. Hypercalcemia from malignancy usually presents more acutely and can progress rapidly. Hypercalcemia in primary hyperparathyroidism tends to have a more insidious onset and may go unrecognized for years. Mild hypercalcemia is typically asymptomatic and often only discovered incidentally on routine labs. When levels rise above 12 mg/dl, symptoms that have coined the mnemonic "stones, bones, abdominal moans, and psychic groans" may begin to appear. Hypercalcemia can slow nerve conduction causing symptoms such as lethargy, depression, and confusion. Muscle contractions are also suppressed, and this can manifest as constipation and weakness. Prolonged hypercalcemia can cause kidney stones and bone demineralization that leads to fractures. Polyuria occurs secondary to the direct effects of hypercalcemia on the kidneys which include diabetes insipidus, increased sodium excretion, and renal vasoconstriction. Calcium deposition in the renal parenchyma can lead to kidney failure. In moderate-to-severe hypercalcemia, cardiac conduction abnormalities including prolonged PR interval, short QT interval, widened QRS complex, bradycardia, and arrhythmias can occur. Levels > 15 mg/dl are considered a medical emergency. [28,32,33]

• References [28,29,30,31,33]

Steps for evaluating hypercalcemia
Step 1 - Evaluate for hyperparathyroidism (> 50% of cases) Confirm that hypercalcemia is real with a repeat calcium level and an ionized calcium Consider medications associated with hypercalcemia (e.g. lithium, thiazide diuretics, abaloparatide, teriparatide, vitamin D and A supplements, antacids) Check serum PTH, phosphorus, and kidney function Elevated or high-normal PTH and high calcium Most patients with hyperparathyroidism will have an elevated PTH, but up to 15% can have a high-normal PTH An elevated PTH in the presence of a high ionized calcium level is diagnostic for primary hyperparathyroidism. A low phosphorus level is also consistent with primary hyperparathyroidism. Refer affected patients for surgical evaluation. Imaging with ultrasound, CT scan, MRI, and nuclear medicine can be performed to locate involved glands. The preferred study depends upon the specialist and availability. If the PTH level is low or low-normal or the above testing is not definitive, proceed to Step 2
Step 2 - Evaluate for malignancy (33 - 50% of cases) Depending on the individual, consider the following cancers and testing: Breast cancer - mammogram or MRI Lung cancer - Chest X-ray or CT scan Renal cancer - ultrasound, CT, or MRI Lymphoma and leukemia - CBC and peripheral smear Multiple myeloma - serum and urine protein electrophoresis Head and neck cancers - CT scan Bone scan - to look for bone metastasis Parathyroid hormone-related peptide (PTHrP) - elevated levels are consistent with malignancy If the above testing is not definitive move to Step 3
Step 3 - Look for less common causes Familial hypocalciuric hypercalcemia - check 24-hour urine for calcium and creatinine. Hyperthyroidism - check TSH Hypervitaminosis A - check vitamin A level Hypervitaminosis D - check calcidiol (25-hydroxyvitamin D) levels Paget's disease - check alkaline phosphatase and order bone scan Granulomatous diseases - chest X-ray and calcitriol levels Adrenal insufficiency - check cortisol level

• Treatment
• The treatment of hypercalcemia is focused on correcting the underlying disorder when possible. Treatments used in select etiologies are reviewed below.

• Severe hypercalcemia (> 14 mg/dl)
• Severe hypercalcemia (> 14 mg/dl) should be addressed promptly with aggressive normal saline infusions, the initiation of an intravenous bisphosphonate, and if necessary, calcitonin. A typical fluid regimen for hypercalcemia consists of a 1 - 2 liter bolus of normal saline followed by 100 - 150 ml/hour titrated to achieve a urine output of 100 ml/hour. Patients without comorbidities (e.g. heart failure, renal failure) may be able to tolerate more, and vice versa. [29]

• Primary hyperparathyroidism
• About 85% of cases are caused by a single adenoma. Surgical removal of the affected glands is recommended in all symptomatic patients. In asymptomatic patients, some experts recommend surgery while others only recommend surgery if one of the following criteria are met:
• Serum calcium > 1 mg/dl above upper limit of normal
• Osteoporosis on BMD or history of vertebral fracture
• GFR < 60 ml/min
• 24-hour urine calcium > 400 mg/day or presence of kidney stones or nephrocalcinosis
• Age < 50 years
• If total parathyroidectomy is performed, a small amount of parathyroid tissue is autotransplanted to the forearm so that calcium regulation is maintained. Additional tissue is also cryopreserved in case the initial transplant does not function properly.
• Transient post-surgical hypocalcemia is seen in about 33% of patients and permanent hypocalcemia occurs in 2% of patients. See hypocalcemia treatment after parathyroidectomy for more. Recurrent hyperparathyroidism occurs in about 10% of cases. [30]

• Malignancies
• Malignancies that cause hypercalcemia cannot always be cured, but there are treatments that can help control the hypercalcemia they induce. The drugs below are used to lower calcium levels in patients with malignancies.

• Bisphosphonates - bisphosphonates inhibit osteoclasts which reduces calcium resorption from bones. Pamidronate and zoledronic acid are intravenous bisphosphonates that are FDA-approved to treat hypercalcemia. In a study of 275 patients, pamidronate was compared to zoledronic acid in patients with hypercalcemia of malignancy (average calcium 14 mg/dl). With both drugs, calcium lowering was seen within 48 hours and normalization of calcium levels occurred in a majority of patients within 4 - 10 days. Zoledronic acid had a longer duration of response when compared to pamidronate (median 32 days vs 18 days). [PMID 11208851] The use of oral bisphosphonates in hypercalcemia of malignancy is less studied. [Pamidronate PI] [Zoledronic acid PI]

• Denosumab (Xgeva®) - denosumab inhibits RANKL, a ligand that stimulates osteoclast activity (see RANKL illustration). Denosumab is FDA-approved to treat hypercalcemia of malignancy that is refractory to bisphosphonates. In a study of patients who failed bisphosphonates, 64% of patients treated with denosumab achieved normal calcium levels by 10 days, and the median duration of response was 104 days. [PMID 24915117] [Xgeva PI]

• Calcitonin - calcitonin is effective for short-term lowering of calcium levels, but its effects begin to wane after 3 days of use. It is often given to lower calcium levels acutely while waiting for the effects of bisphosphonates to take hold. See calcitonin for more.

• Corticosteroids - in conditions where calcitriol is elevated, corticosteroids can help to lower calcium levels. Corticosteroids inhibit the conversion of calcidiol to calcitriol thereby decreasing intestinal calcium absorption. [28,29,33]

• Granulomatous diseases
• Granuloma macrophages possess an enzyme (25-hydroxyvitamin D–1α-hydroxylase) that converts calcidiol to its more active form, calcitriol. This can lead to increased intestinal calcium absorption and hypercalcemia. Corticosteroids inhibit this enzyme and can therefore be used to treat hypercalcemia in granulomatous conditions. For patients with sarcoidosis, hydroxychloroquine may also be used. [28,29]

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• PHOSPHORUS

• Overview
• Phosphorus is a major intracellular anion, and it is involved in a number of physiologic reactions. In the extracellular fluid, it is present in only small amounts. Unlike other electrolytes, it does not have a significant role in tonicity, electrochemical gradients, or acid-base disorders so abnormal levels are typically asymptomatic unless chronic deficiency is present, in which case, osteoporosis and other disorders of bone mineralization may occur. Phosphorus is regulated by the same hormones that regulate calcium, and disorders that affect calcium will typically affect phosphorus too. (see calcium and phosphorus regulation)
• Phosphorus is not part of the typical lab panel, and levels are usually only checked when abnormalities in calcium or kidney function are investigated. The treatment of abnormal phosphate levels is focused on correcting the underlying disorder. Causes of low and high phosphorus levels are discussed below. [2,3,4,40]

• Hypophosphatemia
• Hypophosphatemia is defined as a phosphate level < 2.5 mg/dl in adults. Hypophosphatemia typically occurs through one of three mechanisms: (1) inadequate absorption, (2) increased renal excretion, (3) shift from extracellular to intracellular space.
• Inadequate absorption
• Phosphorus is found in most foods, so inadequate dietary intake is rare. Most phosphorus is absorbed in the proximal small intestine, and this is where gastrointestinal disorders and medications can act to inhibit its absorption. Factors that can decrease phosphorus absorption include the following:
• Chronic diarrhea
• Antacids - calcium, aluminum, and magnesium in antacids bind phosphorus in the intestine and prevent its absorption
• Phosphate-binding agents - see treatment of hyperphosphatemia above
• Vitamin D deficiency - vitamin D has a mild stimulatory effect on phosphorus absorption in the intestines. In extreme cases, vitamin D deficiency may lead to hypophosphatemia.
• Increased renal excretion
• Hyperparathyroidism - PTH stimulates phosphorus excretion
• Primary renal phosphate-wasting syndromes - rare genetic disorders that affect renal phosphate reabsorption (e.g. X-linked hypophosphatemic rickets)
• Fanconi syndrome - in Fanconi syndrome, proximal renal tubular damage prevents reabsorption of glucose, phosphates, and other substances. It may be hereditary or acquired from conditions such as multiple myeloma, Wilson disease, and certain medications.
• Increased diuresis - increased diuresis from diuretics, diabetes insipidus, and osmotic agents (e.g. glucose, mannitol) can cause phosphate loss
• Shift from extracellular to intracellular space
• Refeeding syndrome - refeeding syndrome occurs when a person who has been starved for a period is suddenly fed. The sudden increase in insulin and glucose stimulates cellular metabolism and this drives phosphate uptake by cells.
• Treatment of diabetic ketoacidosis - similar to refeeding syndrome, the sudden increase in insulin stimulates cellular metabolism and this drives phosphate uptake by cells
• Hyperventilation - hyperventilation can lead to hypophosphatemia in extreme cases. In respiratory alkalosis, carbon dioxide shifts out of cells and intracellular pH rises. This causes intracellular phosphate trapping.
• Hungry bone syndrome - after surgical correction of hyperparathyroidism, a sudden decrease in PTH levels can cause bones to undergo rapid remodeling. These "hungry" bones take up lots of phosphorus which can lead to hypophosphatasia [2,41,42]

• Hyperphosphatemia
• Hyperphosphatemia is defined as a phosphate level > 4.5 mg/dl in adults. Hyperphosphatemia typically occurs through one of three mechanisms: (1) decreased renal excretion, (2) excessive phosphate load, (3) shift from intracellular to extracellular space.
• Decreased renal excretion
• Chronic kidney disease - kidney disease is by far the most common cause of hyperphosphatemia. Phosphate levels typically begin to rise when the GFR falls below 30 ml/min. See hyperphosphatemia treatment in CKD for more.
• Tumoral calcinosis - tumoral calcinosis is a rare syndrome marked by calcium salt deposition in periarticular tissue and a deficiency of active fibroblast growth factor 23, a hormone that promotes renal phosphate excretion
• Hypoparathyroidism - loss of PTH-enhanced renal phosphate excretion can cause hyperphosphatemia
• Pseudohypoparathyroidism - rare syndromes where PTH receptors do not respond to the effects of PTH
• Excessive phosphate load
• Tumor lysis syndrome - cell lysis from chemotherapy causes the release of large amounts of intracellular phosphate. Mostly seen with lymphomas and leukemias.
• Rhabdomyolysis - phosphate release from dying muscle tissue
• Severe hemolysis - phosphate release from red blood cells
• Excessive phosphate ingestion - typically from phosphate-containing laxatives
• Hypervitaminosis D - vitamin D increases intestinal phosphate absorption
• Shift from intracellular to extracellular space
• Insulin deficiency (e.g. diabetic ketoacidosis)
• Acute acidosis (e.g. lactic acidosis) [2,39,40]

• Diagnosis
• The cause of abnormal phosphate levels is typically evident from the patient history and/or other laboratories. In rare cases, a 24-hour collection for phosphorus may be required to evaluate renal phosphate excretion. The fractional excretion of phosphate can also be determined from spot urine values with the following formula:
• Fractional excretion of phosphate (FEPO4) = (UPO4 x PCr x 100) / (PPO4 x UCr)
• where UPO4 is urine phosphate, PCr is plasma creatinine, PPO4 is plasma phosphate, and UCr is urine creatinine
• In hypophosphatemia, a 24-hour urine phosphate excretion of < 100 mg or a FEPO4 < 5% indicates renal phosphate retention and suggests decreased phosphate absorption and/or intracellular shifts. A 24-hour urine excretion of > 100 mg or a FEPO4 > 5% indicates renal phosphate wasting which suggests hyperparathyroidism or renal tubular dysfunction.
• In hyperphosphatemia, a FEPO4 < 15% suggests renal failure or hypoparathyroidism. A FEPO4 > 15% suggests excessive phosphate load. [39,40,41,42]

• Treatment
• Hypophosphatemia
• Hypophosphatemia is primarily treated by correcting the underlying disorder. General points about treating hypophosphatemia are presented below
• Dietary phosphorus - Phosphorus is found in most foods, so patients who can eat and absorb phosphorus normally should consume a regular diet. Foods that are high in phosphorus include dairy products, meats, and beans. In most patients, consuming 1000 - 2000 mg of phosphorus per day for 7 - 10 days will replenish phosphorus stores.
• Phosphorus supplements - In some cases (e.g. phosphate-wasting syndromes), a phosphorus supplement may be indicated. Phosphorus supplements like K-Phos Neutral® come in sodium and potassium salts. K-Phos Neutral® contains 250 mg of phosphorus per tablet and the recommended intake is 4 - 8 tablets a day with meals. [K-Phos N Neutral PI]
• Vitamin D - vitamin D enhances phosphate absorption in the intestines and reabsorption in the kidneys. A vitamin D supplement may be used to help increase phosphorus levels.
• Extreme hypophosphatemia or unable to absorb phosphorus - for patients who are unable to absorb phosphorus or have extreme hypophosphatemia, IV phosphorus is indicated

• Hypophosphatemic rickets - some cases of hypophosphatemic rickets are caused by a genetic mutation in fibroblast growth factor 23 (FGF23). FGF23 is a protein that promotes phosphorus excretion in the kidneys. In hypophosphatemic rickets, genetic mutations of FGF23 make it resistant to metabolism, and its activity is increased. A monoclonal antibody to FGF23 called burosumab (Crysvita®) is FDA-approved to treat this condition. It is also approved to treat tumor-induced osteomalacia. [Crysvita PI] [40]

• Hyperphosphatemia
• Hyperphosphatemia is primarily treated by correcting the underlying disorder. The most common cause of hyperphosphatemia is kidney disease. Methods for addressing hyperphosphatemia in kidney disease are discussed above (see treatment of hyperphosphatemia in CKD) [40]

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• MAGNESIUM

• Overview
• Magnesium is the second most abundant intracellular cation, and it is an important cofactor in numerous physiologic processes including metabolism, nerve conduction, receptor activation, and the stabilization of cellular components (e.g. RNA, DNA, cell membrane). The magnesium content in the average adult is about 25 grams with 60% located in bones, 39% inside of cells, and 1% in the extracellular fluid. Sixty percent of extracellular magnesium is present in the free or ionized form, and the remaining 40% is bound to proteins and anions. The average American diet contains about 360 mg of magnesium per day. Under normal conditions, about 33% of dietary magnesium is absorbed, but this can more than double when magnesium stores are depleted. The kidneys are the primary regulators of magnesium excretion; under high loads, they rapidly excrete magnesium, and in deficient states, they can reduce excretion to almost zero. Unlike other electrolytes, magnesium levels do not seem to exert a strong influence on any particular regulatory hormone. [4,43,44]

• Symptoms / ECG
• Symptoms
• Magnesium is required to stabilize neuronal axons, so abnormal levels can affect nerve conduction
• In hypomagnesemia, neuron excitability is increased and symptoms such as tremor, hyperreflexia, fasciculations, muscle cramps, tetany, and in extreme cases, convulsions may occur
• In hypermagnesemia, mild elevations (< 7 mg/dl) are typically asymptomatic. When levels rise above 7 mg/dl, nerve conduction is suppressed and symptoms such as loss of deep tendon reflexes, weakness, hypotension, confusion, ileus, and in extreme cases, paralysis may occur. Magnesium also affects electrical activity in the myocardium through unknown mechanisms, and abnormal levels can cause the ECG changes detailed below. [43,44,45,46]
• ECG changes (hypomagnesemia)
• Widened QRS complex
• Peaked T waves
• Prolonged PR interval
• Premature atrial and ventricular beats
• Atrial fibrillation
• Ventricular arrhythmias including Torsades de Pointes [43,44]
• ECG changes (hypermagnesemia)
• Prolonged PR interval
• Bradycardia
• Atrioventricular block [45,46]

• Diagnosis
• In most cases, the etiology of an abnormal magnesium level is evident from the patient history and/or other laboratories. In rare cases, a 24-hour urine for magnesium may be helpful in distinguishing abnormal renal magnesium handling from other causes. The fractional excretion of magnesium can also be determined from spot urine values using the following formula:
• Fractional excretion of magnesium (FEMg) = (UMg x PCr X 100) / (PMg X 0.7 X UCr)
• where UMg is urine magnesium, PCr is plasma creatinine, PMg is plasma magnesium, and UCr is urine creatinine. PMg is multiplied by 0.7 since about 70% of magnesium is freely filtered in the glomerulus.
• In hypomagnesemia, a 24-hour urine magnesium of > 20 mg or a FEMg > 2% indicates renal magnesium loss and suggests abnormal renal magnesium wasting and/or drug effects (e.g. diuretics, aminoglycosides, cisplatin). A 24-hour urine magnesium < 20 mg or a FEMg < 2% indicates renal magnesium retention and suggests extrarenal losses. [43,44,45,46]

• Hypomagnesemia
• Hypomagnesemia is defined as a magnesium level < 1.5 mg/dl. Hypomagnesemia is present in about 2% of the general population and in up to 20% of hospitalized patients. Alcoholics have the highest incidence with up to 80% affected in some studies. Causes of hypomagnesemia can be divided into three categories: (1) decreased intake/absorption, (2) abnormal renal loss, (3) shift from extracellular to intracellular space.
• Decreased intake/absorption
• Alcoholics (up to 80%) - from decreased intake
• Proton pump inhibitors (e.g. Prilosec, Nexium) - PPIs may reduce magnesium absorption with prolonged therapy (> 3 months)
• Starvation
• Total parenteral nutrition
• Diarrhea
• Vomiting
• Gastric bypass surgery
• Ileostomy - loss of magnesium absorption in the large intestine
• Nasogastric suctioning
• Hypomagnesemia with secondary hypocalcemia - rare genetic disorder that causes nonfunctional magnesium channels in the intestine and kidneys
• Cystic fibrosis - possibly through decreased intestinal absorption and/or renal wasting
• Abnormal renal loss
• Diuretics (most common) - most often seen with loop diuretics because they affect electrochemical gradients in the Loop of Henle where most magnesium is reabsorbed. May also occur with long-term thiazide diuretics and osmotic diuretics.
• Antimicrobials - amphotericin B, aminoglycosides, pentamidine, capreomycin, viomycin, foscarnet
• Chemotherapeutic agents - cisplatin, cetuximab
• Immunosuppressants - tacrolimus, cyclosporine
• Hypercalcemia - hypercalcemia inhibits magnesium reabsorption
• Hyperaldosteronism
• Acute tubular necrosis
• Chronic metabolic acidosis
• Cystic fibrosis - possibly through decreased intestinal absorption and/or renal wasting
• Inherited tubular disorders (Gitelman syndrome, Bartter syndrome)
• Hypomagnesemia with secondary hypocalcemia - rare genetic disorder that causes nonfunctional magnesium channels in the intestine and kidneys
• Other rare genetic disorders
• Shift from extracellular to intracellular space
• Hungry bone syndrome - increased uptake by bones after correction of hyperparathyroidism
• Refeeding syndrome - refeeding syndrome occurs when a person who has been starved for a period is suddenly fed. The sudden increase in insulin and glucose stimulates cellular metabolism and this drives magnesium uptake by cells.
• Treatment of diabetic ketoacidosis - similar to refeeding syndrome, the sudden increase in insulin stimulates cellular metabolism and this drives magnesium uptake by cells
• Hyperadrenergic states (e.g. alcohol withdrawal, post-surgery) - hyperadrenergic states can stimulate magnesium uptake by cells
• Acute pancreatitis - possibly from saponification of magnesium in necrotic fat, similar to what occurs with calcium [43,44]

• Hypermagnesemia
• Hypermagnesemia is defined as a magnesium level > 2.5 mg/dl. Hypermagnesemia is an uncommon laboratory finding because under normal conditions, the kidneys can easily eliminate excess magnesium. Causes of hypermagnesemia can be divided into three categories: (1) increased intake/absorption, (2) decreased renal elimination, (3) shift from intracellular to extracellular space.
• Increased intake/absorption
• Supplements, antacids, and laxatives that contain magnesium oxide, magnesium hydroxide, or magnesium citrate
• Treatment and prevention of eclampsia in pregnant women - magnesium infusions are used to induce hypermagnesemia (4.2 - 8.4 mg/dl) in order to prevent seizures
• Newborns of mothers treated with magnesium
• Gastrointestinal disorders (e.g. gastritis, colitis) - may increase absorption
• Decreased GI motility from anticholinergics or opiates - may increase absorption
• Decreased renal elimination
• Chronic kidney disease
• Lithium therapy - lithium inhibits magnesium excretion
• Milk-alkali syndrome
• Hypothyroidism
• Adrenal insufficiency
• Hyperparathyroidism - secondary to calcium-induced magnesium absorption in the tubule
• Familial hypocalciuric hypercalcemia - rare disorder that can sometimes cause hypermagnesemia (see familial hypocalciuric hypercalcemia above)
• Shift from intracellular to extracellular space
• Tissue breakdown (e.g. shock, burns)
• Tumor lysis syndrome
• Massive hemolysis
• Rhabdomyolysis
• Metabolic acidosis [45,46]

• Treatment
• Hypomagnesemia
• In hospitalized patients with severe (< 1.2 mg/dl), symptomatic hypomagnesemia, IV magnesium is indicated. Most patients with hypomagnesemia are asymptomatic and can be treated with oral supplements or dietary magnesium. General points about magnesium replacement are given below. [43,44]

• Diuretic-induced hypomagnesemia - diuretic-induced hypomagnesemia can be treated with dietary magnesium, magnesium supplements, and/or the addition of an ENaC inhibitor (amiloride or triamterene). ENaC inhibitors promote magnesium retention in the renal collecting duct (see magnesium retention with ENaC inhibitors for more). [44]

• Dietary magnesium - increased intake of dietary magnesium can help to replenish stores. The recommended dietary allowance for magnesium in adults is around 420 mg/day in males and 320 mg/day in females. See foods sources of magnesium for a list of foods that are high in magnesium. The USDA food composition database also contains the magnesium content of thousands of foods. [44,48,49]

• Magnesium supplements - magnesium supplements are available in many different formulations in a large number of over-the-counter products. There are no consensus guidelines or good studies that offer guidance on dosing or choosing a magnesium supplement. Magnesium absorption in the intestines is incomplete, and studies have shown that different formulations of magnesium can vary widely in their amount of bioavailable magnesium. The National Institute of Health states that the upper limit of tolerability for magnesium supplements in adults is 350 mg of elemental magnesium per day; supplementation that exceeds this amount will likely cause diarrhea and intolerable gastrointestinal side effects. That being said, most magnesium supplements provide low levels of bioavailable magnesium, so doses above this level are often used. The table below shows the properties of available magnesium supplements. Supplement dosing and length of therapy will depend upon the degree of deficiency and whether the underlying etiology has been corrected. Patients with significant kidney disease (GFR < 30 ml/min) are at increased risk of hypermagnesemia and should be started at half the typical dose with close monitoring. Only a handful of studies have measured the effects of magnesium supplements on magnesium levels, and those studies are included in the table below. [43,44,47,48,49]

• Hypermagnesemia
• Symptomatic, severe hypermagnesemia (> 12 mg/dl) should be treated with intravenous calcium, because calcium blocks the neuromuscular and cardiovascular effects of magnesium. Normal saline infusions and loop diuretics can help to enhance the excretion of magnesium. In severe cases, hemodialysis may be necessary. [44,45]

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