Disorders of Potassium, Magnesium, and Calcium Balance

Also known as: Hyperkalemia, Hypokalemia, Hypermagnesemia, Hypomagnesemia, Hypercalcemia, Hypocalcemia

Related conditions: Malnutrition, Acid-Base Disorders, Renal Failure Acute and Chronic, Hyperaldosteronism Primary and Secondary, Hypoaldosteronism Primary and Secondary, Adrenal tumors, Hyperparathyroidism Primary and Secondary, Hypoparathyroidism Primary and Secondary, Parathyroid tumors

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1. Description of the problem

1. Disorders of Potassium

K is an essential intracellular cation; 98% of total body K is intracellular. It is a main determinant of intracellular osmolality, and its transmembrane gradient regulates cell membrane resting electrical potential.

Intracellular concentration of K (100 to 150 mEq/L) is maintained via an active Na/K ATPase membrane active transport system, which extrudes 3 Na+ ions from the cell and transports 2 K+ ions intracellularly against a steep K concentration gradient.

Na/K ATPase is stimulated by catecholamines and insulin, and its function is also dependent on thyroid hormones. Catecholamines inhibit intracellular entry of K via α-receptors and stimulate intracellular entry of K via β2-receptor stimulation of Na/K ATPase. Insulin stimulates Na/K ATPase and promotes intracellular K entry. The primary physiologic effect of insulin and catecholamines is to facilitate the disposition of a K load. The ability to handle a K load is impaired in insulin deficiency.

Aldosterone promotes intracellular K entry and renal and intestinal excretion of K. Thyroid hormones, glucocorticoids and growth hormones maintain long-acting stimulation of Na/K ATPase. K is normally released from muscle cells during exercise in proportion to the intensity of exercise. Normally, the elevation in K level is transient and mild, but may be exacerbated to dangerous levels in patients on β-blockers.

Intracellular K diffuses passively across cell membranes; the magnitude of K transmembrane diffusion determines transmembrane electrical potential. Intracellular entry of K is related to insulin-dependent intracellular transport of glucose and transmembrane H+ gradients.

In metabolic acidosis, ~60% of H+ ions are buffered intracellularly and K exits the cell, in exchange for H+.

As a rule of thumb, for each 0.1 decrease in plasma pH, plasma K increases by ~0.6 (0.2-1.7) mEq/L

Organic acidosis such as lactic and ketoacidosis are associated with lesser degrees of hyperkalemia than mineral acidosis.

In metabolic alkalosis, K shifts intracellularly in exchange for H+ . Hyperosmolality may cause extracellular K shifts, such as in severe hyperglycemia and after rapid intravenous administration of sodium bicarbonate. Plasma K concentration may rise as much as 0.4 to 0.8 mEq/L for every 10 mOsm/kg increase in effective plasma osmolality. Extracellular concentration of K (3.5 to 5.0 mEq/L) is small and tightly regulated

Abnormalities in extracellular K concentration may result in severe cardiac arrhythmias and skeletal muscle dysfunction.

The two pathways of excretion of K are intestinal and renal. Renal K excretion is tightly regulated to maintain balance between intake and output and stable K body contents. In adults, intake and output is usually equal and approximately 1.5 mEq/kg/day. Renal K excretion is primarily stimulated by three factors:

  • Increase in serum K concentration

  • Increase in serum aldosterone concentration. Aldosterone increases the number of open apical cell sodium channels; increased Na reabsorption increases the electronegativity of the lumen and therefore enhances K secretion.

  • Enhanced delivery of sodium and water to the distal secretory site.

A K load is usually excreted in the urine in 6 to 8 hours in patients with normal renal function. Virtually all the K excreted in the urine is K secreted in the renal tubules; virtually all filtered K is reabsorbed completely in the proximal tubule and thick ascending loop of Henle (TALH). Renal excretion of K is regulated by modifying K tubular secretion. Renal tubular handling of K is closely associated with renal control of acid-base equilibrium

Renal tubular handling of K is tightly regulated by the renin-angiotensin-aldosterone axis. K filters freely across the glomerular filtration membrane.

As tubular fluid moves along the proximal tubule, K is actively transported outside of the tubular fluid in association with active Na and passive water transport such by the end of the proximal tubule, little K (30%-50%) remains in the tubular fluid. The remaining K in tubular fluid is virtually completely reabsorbed in the thick ascending loop of Henle, in a process that can be inhibited by loop diuretics.

Within the thick ascending loop of Henle, the majority of K reabsorption is mediated via the apical membrane furosemide-sensitive Na/K/2Cl cotransporter (NKCC2), whose activity is driven by the basolateral Na/K ATPase. Apical secretory K channels recycle K intra- and extracellularly and maintain an intratubular-positive transepithelial electrical gradient, which favors Ca and Mg reabsorption.

In the distal and cortical collecting duct, K is passively secreted into the tubular fluid in exchange with Na reabsorption and along with H+ secretion. In the distal and cortical collecting tubule two morphologically distinct cells, the principal cells (PC) and the intercalated cells (IC) are responsible for K secretion and reabsorption, respectively. IC are capable of significant reabsorption of K during periods of K depletion.

Apical entry of Na via the epithelial Na channel (ENaC) generates a lumen-negative transepithelial potential that drives K exit via apical channels. Distal K secretion is critically dependent on distal Na delivery

In the distal nephron, K is recirculated such that K secreted in the cortical collecting duct is reabsorbed in the outer and innner medullary collecting duct and secreted into the thin descending loop of Henle (medullary K recycling). This recirculation causes high medullary K concentration and contributes to a lumen-negative transepithelial gradient that favors K secretion.

Potassium channels

Low conductance channel (renal outer medulla K; SK/ROMK) restricted to the PC. Mediates baseline K secretion and is stimulated by increased tubular flow such as in volume expansion or diuretic therapy; mediates adaptive increases in K excretion. Blockade of this channel prevents K recycling via the apical membrane and secondarily inhibits Na/K/2Cl cotransport in the thick ascending loop of Henle, causing a picture similar to loop diuretic effects or Bartter syndrome. SK/ROMK channels are sensitive to intracellular pH such that an intracellular pH of 7.0 inhibits channel activity.

High-conductance Ca2+ -activated channel (BK/maxi-K). Mediates flow-stimulated K secretion in connecting tubule and cortical collecting duct. It is activated by increased intracellular concentration of Ca2+, transducing increased tubular flow such as during diuretic effects or volume expansion. BK/maxi-K channels become important when SK/ROMK channels are blocked. Regulates distal K transport.

Sodium delivery

Extracellular volume expansion or diuretic administration enhances K secretion. Main mechanisms include increased distal delivery of Na, which facilitates K exchange and activation of BK/maxi-K channels. Concurrent reabsorption of Cl- reduces transepithelial electrical gradient and limits K secretion. When lesser reabsorbable anions such as bicarbonate or ketoacids (such as in diabetic or fasting ketoacidosis) accompany Na, intratubular electronegativity increases and K secretion increases. Penicillins are also nonreabsorbable anions that can induce increased K secretion and hypokalemia.

Acid-base balance

In acute metabolic acidosis intracellular buffering of H+ induces hyperkalemia due to a shift of K to the extracellular space in exchange for H+. Decreased intracellular pH inhibits the SK/ROMK channel and decreases K urinary excretion, thus worsening the trend to hyperkalemia. In acute metabolic and respiratory alkalosis, renal K excretion increases due to basolateral intake of K and increased activity of the BK/ROMK channel.


The magnitude of renal K excretion is adjusted to dietary K intake within 1 to 2 days. High K dietary intake stimulates aldosterone secretion, which in turn stimulates Na/K ATPase and ENaC as well as the high- and low-conductance K channels. Low dietary K intake reduces renal and intestinal K excretion within 24 hours

Higher H+ excretion results in metabolic alkalosis.

Vasopressin stimulates K secretion via V2 basolateral receptors activating ENaC,which results in greater K apical secretion and activation of SK/ROMK channels.

Distal tubular secretion of K is stimulated by aldosterone. Aldosterone-receptor competitive inhibitors such as spironolactone and eplerenone decrease renal K excretion.

Distal tubular secretion of K can be blocked by K-sparing diuretics such as amiloride and triamtirene, which block apical cell Na channels. Trimethoprim (a component of the combination chemotherapeutic agent trimethoprim/sulfamethoxazole) has similar effects to those of triamtirene and blocks K secretion, thus increasing the risk of hyperkalemia.

Intracellular depletion of K stimulates tubular H+ secretion and tubular secretion of ammonia, thus inducing metabolic alkalosis and hyperammonemia

2. Metabolism of magnesium

Mg is a divalent cation atomic weight 24 that serves as an important cofactor to numerous enzymes, especially those involving ATP. Mg homeostasis is largely controlled by the kidney. Serum Mg concentration may not reflect the status of total body Mg. During Mg depletion, the urinary fractional excretion (FEMg) is less than 2%. Magnesium metabolism disturbances are associated with important consequences on membrane stability, hormone secretion and neuromuscular and cardiovascular function.

Distribution of body magnesium

Mg is distributed 66% in the skeleton, 33% in intracellular (muscle and liver), 1% extracellular. Serum Mg: normal range 1.6 to 2.4 mg/dL (1.4-2 mEq/L, or 0.7-1.0 mMol/L). The ionized portion is a physiologically active moiety: 55% to 70% of total serum Mg. Mg is protein bound 20% to 30%, complexed 10% to 20%. Total serum Mg levels correlate well with clinical manifestations quite independently of serum albumin levels.

Tissue Mg: one third on the surface of hydroxyapatite crystals, two thirds intracellularly within organelles, especially mitochondria. Control of intracellular Mg is poorly understood.

Magnesium homeostasis

Normal Mg ingestion is ~300 mg/day, digestive secretions 30 mg, net absorption 30% (~100 mg), usually balanced by similar urinary excretion. Mg absorption is not regulated; balance is maintained by renal excretion. Magnesium depletion is unusual except in patients with severe malnutrition and is a common problem in severe alcoholics.

Most intestinal absorption is in the ileum. The nonsaturable component is quantitatively the most important. The role of vitamin D in Mg transport is controversial. Phosphate binders limit Mg absorption.

Renal handling

Urinary excretion is the net result of glomerular filtration and tubular reabsorption. Mg balance is achieved by changes in Mg reabsorption. Mg is filterable 80% (2000 mg/day), ~100 mg/day are excreted in the urine (1%-3%)

During Mg depletion urinary excretion can decrease to less than 0.5%of the filtered load.

The proximal tubule reabsorbs 10% to 15% of the filtered load. The thick ascending loop of Henle is responsible for ~70% of tubular reabsorption, driven by transepithelial lumen-positive electrical gradient generated by K recycling. In the thick ascending loop of Henle and distal tubule, the calcium sensor receptor CaSR regulates Ca and Mg reabsorption. Distal tubule reabsorption (10%) is active and regulates Mg excretion. Driven by electrical gradient, Mg enters the cell via the divalent ion channel TRPM6.

Regulation of magnesium metabolism

The important divalent sensing receptor CaSR in the TALH responds to changes in plasma magnesium and calcium concentrations with a decrease in paracellular transport by affecting paracellin-1: this is the most important mechanism by which hypomagnesemia stimulates Mg conservation. See Table I.

Table I.
Agent or Condition Tubular Reabsorpton TALH Tubular Reabsorption Distal Tubule
Parathyroid hormone Increase Increase
Calcitonin Increase Increase
Vasopressin Increase Increase
1,25(OH)2 vit D ? Increase
Aldosterone Increase Increase
Insulin Increase Increase
Hypomagnesemia Increase Increase
Hypermagnesemia Decrease Decrease
Hypercalcemia Decrease Decrease
Volume expansion Decrease Decrease
Potassium depletion Decrease Decrease
Hypophosphatemia Decrease Decrease
Metabolic acidosis Decrease Decrease
Metabolic alkalosis Increase Increase
Loop diuretics Decrease No effect
Thiazide diuretics No effect Increase
Amiloride No effect Increase

TAHL=Thick ascending loop of Henle; 1,25(OH)2D=Calcitriol.

Modified from: McKay CP. Disorders of magnesium metabolism. In: Feld LG, Kaskel FJ (eds). Fluid and electrolytes in pediatrics. New York: Humana Press, a part of Springer Science+Business Media; 2009, p 149.

3. Metabolism of Calcium

The majority (99%) of Ca is located in bone. Three organ systems are involved in the transport of Ca into the extracellular fluid: gastrointestinal, renal and bone. Two interdependent endocrine systems are responsible for the control of extracellular calcium levels: parathyroid hormone (PTH) and the vitamin D metabolite 1,25(OH)2 vitamin D3.

Hypercalcemia generally results from increased gastrointestinal absorption, decreased renal excretion or imbalance between osteolysis and osteogenesis. In adults, the two main causes of hypercalcemia are hyperparathyroidism and malignancy, and immobilization in the elderly.

Body distribution of Ca

  • 99% in bone as hydroxyapatite, approximately 1300 g in the adult

  • 1% distributed between teeth, soft tissues and extracellular space. The 1 g of Ca in the plasma and extravascular space is tightly regulated by PTH and vitamin D.

Serum Ca

Normal range 9.0 to 10.5 mg/dL: 50% ionized (free); 40% protein bound ( 75%-90% albumin); 10% complexed with plasma anions such as phosphate, citrate, bicarbonate and lactate. The degree of Ca binding to albumin can be altered by:

  • Albumin concentration. Each g of albumin binds 0.8 mg of calcium.

  • Complexing anions

  • Plasma pH: Alkalemia increases the percentage of Ca bound to albumin. Acidemia displaces Ca from albumin.

Transmembrane movement of Ca

While extracellular concentration of Ca++ is 10-3 M; cytosolic concentration is kept at 10-6 M by active transport systems and binding of Ca to cytosolic molecules. The two major mechanisms are the Na/Ca exchanger (NCX) and the Ca++ -ATPase (PMCA).


The amount of Ca entering the body via the intestine equals the amounts deposited in bone and excreted by the kidney and sweat.

Calcium transport: Intestine

Ca absorption is usually 30% of normal dietary intake (20%-60%) depending on intake and age. Ca absorption occurs by passive and active transport stimulated by 1,25(OH)2 vit D. Active transport occurs in the duodenum and upper jejunum (90%). Young age, low Ca and P intake, vitamin D, and PTH via 1,25(OH)2D increase Ca absorption. Glucocorticoids decrease Ca absorption

Calcium transport: Kidneys

Ionized and complexed fractions of Ca filter freely across the membrane (filterable fraction 60% of plasma Ca). Normally, 98% of the filtered load is reabsorbed resulting in normal Ca excretion of 150 to 200 mg/day in the adult. in children bone Ca accretion exceeds renal excretion, resulting in positive Ca balance.

Tubular reabsorption of Ca

65% proximal; 20% thick ascending loop of Henle; 10% distal tubule; 2% collecting tubule. The proximal tubule is responsible for the majority of Ca reabsorption via solvent drag, passive and paracellular mechanisms, active transport in S3 segment. The magnitude of proximal reabsorption is tightly related to Na transport.

The TALH is an important regulator of Ca reabsorption; it is the site of regulation of Ca excretion by PTH and calcitonin. Reabsorption is coupled to sodium and blocked by loop diuretics. Loop diuretics inhibit the Na-K-2Cl transporter

Distal tubule reabsorption is disassociated from Na transport. Transport is all transcellular and against a concentration gradient. Apical entry by Ca channels PTH and calcitonin are dependent; exit via vitamin D-dependent calcium-binding protein calbindin D28K. Reabsorption is stimulated by thiazide diuretics.

Connecting and collecting tubule transport is stimulated by amiloride.

Calcium transport: Bone

Two Ca pools: rapidly exchangeable and slow exchangeable pool

Bone formation (osteogenesis) and reabsorption (osteolysis) are tightly coupled

PTH induces activation of macrophages into osteoclasts and, secondarily, osteoblast activation resulting in increased bone turnover and predominant lytic activity

Regulation of Ca metabolism

Parathyroid hormone (PTH) is the primary regulator of Ca metabolism. The primary regulator of PTH secretion is serum Ca level, which inhibits PTH secretion via the Ca-sensing receptor CaSR. 1,25(OH)2 vitamin D inhibits PTH secretion via the vitamin D receptor. High phosphate blood levels inhibit PTH secretion. The actions of PTH are mediated by the PTH/PTHrP receptor protein, expressed in multiple tissues.

Kidney and bone are the main effectors of PTH. In bone, PTH stimulates the differentiation of osteoblasts into osteoclasts, leading to release of Ca from bone pools. In the kidney, PTH receptors are distributed throughout the nephron. PTH stimulates Ca reabsorption in the TALH and distal tubule, phosphate excretion and 1′-hydroxylase activity leading to the formation of 1,25(OH)2 D.

By promoting hypercalcemia, elevated PTH levels may actually lead to hypercalciuria due to hypercalcemia and increased Ca filtered load as Ca is released from bone and intestine. In response to hypocalcemia, PTH promotes release of Ca and P from bone and, via 1,25(OH)2D, increased intestinal absorption of Ca and P.

Vitamin D: Absorbed and synthesized vitamin D is first 25-hydroxylated in the liver and subsequently 1′-hydroxylated in the renal tubule to become 1,25(OH)2D, the active form. 1,25(OH)2D promotes Ca and P absorption in the intestine and is essential to permit bone mineralization.

Calcitonin is secreted by C cells in the thyroid to control hypercalcemia; it has a limited role in Ca metabolism control.

Parathyroid-related peptide (PTHrP) is part of the PTH gene family and can activate the PTH receptor. In the fetus it promotes cartilage and teeth growth. In the pregnant and lactating mother, it promotes lactation and Ca transport into breast milk. In the adult, it is the main mediator of hypercalcemia of malignancy.

2. Emergency Management

Disturbances in K balance

Body K stores can become abnormal either owing to abnormal intake or abnormal losses, primarily renal or intestinal. Serum K can become abnormal owing to abnormal body K stores or abnormal transmembrane distribution of K (K shifts).

Clinical assessment of urinary K excretion

The most accurate measure, 24-hour urinary K collection, is affected by practical problems such as incomplete collection. Random urinary K, however, is misleading as it is affected by urinary concentration and dilution. K depletion causes polyuria and a deceivingly low K urinary concentration. Urinary K-to-creatinine concentration ratio (K/Cr) can be used because Cr excretion is nearly constant (~20 mg/kg/day) but it is dependent on glomerular filtration rate and muscle mass.

Another measure is fractional excretion of K (FEK). FEK = (Urine [K] X Plasma [Cr]) / (Plasma [K] X Urine [Cr]) X 100. Average dietary intake FEK=10%.

In extrarenal K loss, hypokalemia and FEK are less than 7%; renal K loss, hypokalemia and FEK are greater than 7%.The most accurate estimation of K excretion is transtubular K gradient (TTKG). TTKG = {Urine[K] / (Urine osmolality / Plasma osmolality)} / Plasma [K].

This formula adjusts K excretion to plasma K and renal urinary concentration/dilution. The average dietary intake TTKG 8 to 9; K load TTKG, greater than 11.

Hyperkalemia due to renal retention, TTKG less than 5 to 7.

IMPORTANT: To assess whether inappropriately low TTKG in the face of hyperkalemia is due to intrinsic tubular dysfunction or hypoaldosteronism, repeat TTKG 1 hour after administration of 0.1mg of fludrocortisone. If TTKG increases above 10, treatment with fludrocortisone is indicated; otherwise, increased distal tubular delivery of sodium such as that induced by loop diuretics may be indicated.

Evaluation of total body Mg stores

Evaluation of renal Mg handling: To test whether there is appropriate renal Mg conservation or if the kidney is responsible for Mg depletion, fractional excretion of Mg (FEMg) can be measured in spot urine:

FEMg = UMg X PCr/0.7 X PMg X UCr X 100, where U=urine; P=plasma; Cr=creatinine. In nonrenal disorders causing hypomagnesemia: FEMg is less than 2%. In renal Mg loss: FEMg greater than 5% and often greater than15%.

3. Diagnosis

Symptoms of Hypokalemia

Subjective: palpitations, muscle cramps, paralysis, constipation, nausea or vomiting, polyuria, nocturia, mental status changes. Clinical manifestations are uncommon unless serum K is less than 3 mEq/L, generally earlier and more severe if hypokalemia is acute.

Life-threatening: Rhabdomyolysis and diaphragmatic weakness.

Cardiac arrhythmia: EKG changes: T wave flattening, inverted T wave, prominent U wave, ST segment depression, atrial or ventricular arrhythmia

– Epinephrine released during a stress response such as acute coronary ischemia drives K intracellularly and may increase the risk of ventricular arrhythmia.

– Impaired urinary concentration and polyuria due to decreased tubular vasopressin responsiveness

– Increased renal ammonia production and increased net acid secretion causing metabolic alkalosis

– Inability to eliminate a Na load and fluid retention

Chronic: Hypokalemic nephropathy with interstitial fibrosis and tubular atrophy

Hypokalemia and Acid-base disorders

The minimal urinary K concentration achievable is 5 to 15 mEq/L. Metabolic acidosis with low urinary K will likely lower GI losses due to diarrhea. Metabolic acidosis with high urinary K is likely due to diabetic ketoacidosis or renal tubular acidosis 1 or 2. Metabolic alkalosis with high urinary K and normotension is likely due to vomiting or diuretics or Bartter or Gitelman syndrome. Urinary Cl is low in vomiting and high in Bartter or Gitelman. Urinary Cl is high during diuretic effects, low in postdiuretic effects.

Symptoms of Hyperkalemia

Clinical manifestations are due to change in the impaired neuromuscular transmission and altered membrane electrical potential. Hyperkalemia initially determines hyperexcitability of plasma membrane, but persistent depolarization inactivates sodium channels and leads to late decrease in membrane excitability, leading to muscle weakness or paralysis.

EKG changes: Tall peaked T wave is the earliest change, followed by shortened QT interval. At higher K levels, there is progressive lengthening of the PR interval and QRS duration. Progressively, P waves disappear and ultimately the QRS widens to form a sine wave, leading to ventricular arrest with flat EKG line.

Conduction abnormalities include right and left bundle branch and bifascicular block, and advanced atrioventricular block. Cardiac arrhythmias include sinus bradycardia, sinus arrest, slow idioventricular rhythms, ventricular tachycardia, and fibrillation and ventricular asystole.

Progression and severity of EKG changes do not correlate with serum K concentration. Clinical manifestations occur most frequently at serum levels greater than 7 mEq/L with chronic hyperkalemia or at lower levels in acute hyperkalemia. Hyperkalemia may cause metabolic acidosis such as in renal tubular acidosis type IV, in which hyperkalemia inhibits renal ammonium (NH4) excretion.

Symptoms of Hypomagnesemia

Hypomagnesemia is a very common and important condition, generally underestimated by serum Mg levels

It is caused by decreased intestinal absorption, decreased renal tubular reabsorption causing urinary loss.

Definition: Mg levels less than 1.6 mg/dL (1.4 mEq/L or 0.7 mM). The characterization of the status of total Mg body stores is difficult.

Neuromuscular effects

  • Neuromuscular excitability

  • Trousseau’s sign: sphygmomanometer cuff at 20 mmHg above systolic blood pressure causes carpal spasm

  • Chvostek’s sign: preauricular tapping of facial nerve causes twitching of nasolabial fold and lip, lateral eye angle and homolateral facial muscles

  • Seizures

  • Vertigo, chorea, ataxia, psychiatric changes

  • Vertical nystagmus

Cardiac effects

Conduction disturbances

EKG changes:

  • Prolonged PR and QT intervals

  • Widening of the QRS complex

  • Abnormal T and U waves

  • Atrial and ventricular arrhythmia including Torsade des Pointes

Exacerbation of digoxin toxicity

Role in myocardial infarction

Concurrent electrolyte disturbances


  • Seen with severe hypomagnesemia less than 1.1 mg/dL

  • Associated with hypoparathyroidism due to Mg depletion due to decreased PTH secretion and decreased response to PTH

  • Hypokalemia

  • Closely interrelated phenomena

Symptoms of Hypermagnesemia

Clinically significant hypermagnesemia is uncommon in the presence of normal renal function. Hypermagnesemia is almost always the result of either decreased renal function or increased enteral or parenteral Mg load. Definition: Serum Mg greater than 2.4 mg/dL (2 mEq/L or 1 mM). The clinical presentation is related to the degree of hypermagnesemia and is usually not evident until Mg levels are greater than 3 to 5 mg/dL.

Serum Mg 3 to 5 mg/dL

  • Mild hypotension

  • Drowsiness, lethargy

  • Flushing

  • Nausea and vomiting

Serum Mg 5 to 10 mg/dL

  • EKG changes: prolongation PR, QRS and QT intervals

  • Hypotension

  • Decreased deep tendon reflexes

  • Hypoventilation

  • Severe hypermagnesemia (serum Mg >10 mg/dL) can cause hypocalcemia by suppressing PTH secretion.

  • Coma

  • Muscle paralysis

  • Respiratory paralysis

  • Refractory hypotension

  • Complete heart block

  • Cardiac arrest

Hypomagnesemia: Diagnostic evaluation
Clinical manifestations of hypomagnesemia


  • Trousseau’s and Chvostek’s signs

  • Muscle tremor

  • Muscle weakness

  • Vertical nystagmus

  • Seizures


  • EKG changes: Prolonged PR and QT interval

  • Arrhythmia: Supraventricular, ventricular

  • Sudden death

  • Enhancement of digoxin toxicity

  • Hypertension

  • Electrolyte: Hypokalemia, hypocalcemia

Calcium disorders: diagnostic evaluation

Understanding Ca disorders requires simultaneous measurement of Ca, P and Mg. Formulas “correcting” Ca by albumin levels are inaccurate. In the critically ill patient with Ca disorders it is best to directly measure ionized calcium.

Measure PTH

“Intact” PTH levels are the most accurate to evaluate parathyroid function. Normal levels 10 to 65 pg/mL. Correlate PTH levels with simultaneous blood Ca levels. PTH levels below 25 pg/mL in 70% to 80% of patients with non-PT hypercalcemia and greater than 65 pg/mL in 90% of patients with primary hyperparathyroidism.

Measure 25-OH and 1,25(OH) vitamin D levels

25-OH D is the major circulating form of vitamin D and its levels reflect vitamin D body stores. Normal levels, 10 to 80 ng/mL, vary with the season and latitude. Vitamin D deficiency: 25-OHD levels less than 8 ng/mL; vitamin D intoxication: 25-OH greater than 200 ng/mL

Levels of 1,25(OH)2 D reflect highly regulated renal synthesis of the active metabolite. Normal levels are 20 to 60 pg/mL and are not affected by season or latitude. Levels are decreased in renal dysfunction and in type 1 vitamin D-deficient rickets (lacking 1′-hydroxylase). Levels are abnormally increased in granulomatous diseases including sarcoidosis and lymphoma. Vitamin D-dependent rickets type 2 (vitamin D receptor dysfunction causing secondary hyperparathyroidism).

Skeletal evaluation with bone density studies and radiology may help in management. High levels are associated with cancer and the syndrome of humoral hypercalcemia of malignancy: Severe hypercalcemia, hypophosphoremia, suppressed PTH and elevated PTHrP greater than 5 pmol/L PTHrP when indicated: normal levels less than 1 pmol/L.

Evaluation of renal function is essential to understand Ca metabolism disorders. Normal renal Ca excretion: 4 mg/kg body weight/day. Ca/creatinine ratio in urine varies by age; in adults it is less than 0.25 mg/mL.

– Hypercalciuria: vitamin D-induced hypercalcemia, primary hyperparathyroidism, immobilization and malignancy.

– Hypocalciuria: vitamin D deficiency, malabsorption, hypoparathyroidism and familial hypocalciuric hypercalcemia.

Clinical manifestations of hypocalcemia


Prolonged QT interval on EKG, heart failure


  • Paresthesias, perioral tingling

  • Muscle cramps, tetany

  • Laryngospasm

  • Trousseau’s sign

  • Chvostek’s sign

  • Seizures

  • Papilledema

  • Irritability, changes in mental status

  • Basal ganglion calcification

(See Table II)

Table II.
Condition Phosphate PTH Vitamin D
Hypoparathyroidism High Low 1,25vitD nl or low
Pseudohypoparathyroidism High High 1,25vitD nl or low
Tumor lysis syndrome High High nl
Vit D deficiency Low High 25OHvitD Low
Vit D dep. rickets Type 1 Low High 1,25vitD Low
Vit D dep. rickets Type 2 Low High 1,25vitD High
Hypomagnesemia nl to High Low 1,25vitD nl or low

PTH=Parathyroid hormone; 25OHD=Calcidiol; 1,25(OH)D=Calcitriol; Vit D=Vitamin D. Modified from McKay CP. Disorders of calcium metabolism. In: Feld LG, Kaskel FJ (eds). Fluid and electrolytes in pediatrics. New York: Humana Press, a part of Springer Science+Business Media; 2009, p 105.

Clinical manifestations of hypercalcemia

Hypercalcemia is a relatively common clinical problem. The two most common causes (>90%) are malignancy and primary hyperparathyroidism. The most common manifestation of hypercalcemia is polyuria.

Clinical manifestations vary depending on the severity of hypercalcemia and time course of onset:

– Calcium less than 12 mg/dL (3 mM/L): Generally asymptomatic or nonspecific symptoms—constipation, fatigue, depression.

Calcium 12 to 14 mg/dL (3 to 3.5 mM): Well tolerated chronically but acutely causes severe symptoms:

– Polyuria, polydipsia, dehydration

– Anorexia, nausea and vomiting

– Muscle weakness

– Changes in sensorium

– Calcium >14 mg/dl (3.5 mM)

– Same symptoms, progressively more severe including stupor and coma

Calcium manifestations by organ system

Neuropsychiatric manifestations: increasing in severity proportional to the degree of hypercalcemia.

Gastrointestinal manifestations: In addition to nausea and vomiting, patients may develop acute pancreatitis and peptic ulcer disease, presumably due to hypercalcemia-induced gastrin secretion. In patients with MEN1, Zollinger-Ellison syndrome is associated with hypergastrinemia and gastric ulcer and hyperparathyroidism.

Renal dysfunction

  • Nephrogenic diabetes insipidus (up to 20%)

  • Downregulation of aquaporins by prolonged hypercalcemia

  • Dehydration exacerbates hypercalcemia and renal dysfunction

  • Nephrolithiasis due to chronic hypercalcemia and hypercalciuria

  • Renal tubular acidosis type 1 (distal) infrequently

Renal insufficiency: Moderate hypercalcemia 12 to 15 mg/dL can lead to reversible decrease in glomerular filtration rate due to vasconstriction and natriuresis-induced volume contraction. Long-standing hypercalcemia and hypercalciuria may lead to nephrocalcinosis and interstitial fibrosis, predominantly medullary. Hypercalcemia is the most common cause of renal insufficiency in patients with sarcoidosis.

Cardiovascular manifestations: Shortening of the myocardial action potential leads to decreased QT interval. ST elevation mimicking myocardial infarction has been described

Musculoskeletal manifestations: Muscle weakness, bone pains due to either metastasis or primary hyperparathyroidism.

4. Specific Treatment


Decreased K intake can lead to total body depletion of K and hypokalemia, defined as plasma K less than 3.5 mEq/L Hypokalemia can lead to cardiac arrhythmia, especially among persons treated with digitalis. Administration of diuretics is a common cause of K depletion and hypokalemia. Metabolic alkalosis shifts K intracellularly, in exchange for H+ exit from cells.

Severe vomiting can lead to hypokalemia and metabolic alkalosis; in this case, the main source of K loss is not in the vomit but in the urine, as a result of the metabolic alkalosis, secondary hyperaldosteronism and—in later stages of prolonged vomiting—urinary potassium bicarbonate excretion.

Primary and secondary hyperaldosteronism are associated with hypokalemia and metabolic alkalosis. Excessive diarrheal loss of K can lead to hypokalemia and hyperchloremic metabolic acidosis due to intestinal lossof bicarbonate. Rare congenital abnormalities such as Bartter syndrome and Gitelman syndrome induce metabolic alkalosis and hypokalemia.


Hyperkalemia is rare in subjects with normal renal function As renal dysfunction progresses, the risk of hyperkalemia increases because the kidneys lose the ability to adjust the magnitude of K tubular secretion to the needs of body balance. Hypercatabolic situations such as sepsis and high fever are frequently associated with hyperkalemia.

Intra-intestinal erythrocyte breakdown in situations of gastrointestinal bleed frequently leads to hyperkalemia due to sudden body load of K due to intestinal absorption. Obstructive uropathies lead to disproportionate degrees of hyperkalemia, primarily due to renal medullary injury and decreased prostaglandin medullary production.

Drugs are a main mechanism of hyperkalemia. Non-steroidal antinflammatory drugs may cause hyperkalemia either because they induce gastritis and GI bleed or because they decrease renal function and block intrarenal prostaglandin synthesis. ACEIs and ARBs induce hypoaldosteronism and decreased tubular K secretion. Distal tubular secretion of K can be blocked by K-sparing diuretics such as amiloride and triamtirene, which block apical cell ENaC channels.

Trimethoprim (a component of the combination chemotherapeutic agent trimethoprim/sulfamethoxazole) has similar effects to those of triamtirene and blocks K secretion, thus increasing the risk of hyperkalemia

Aldosterone-receptor competitive inhibitors such as spironolactone or eplerenone decrease renal K excretion.

Massive muscle breakdown such as in crush syndrome can be associated with life-threatening hyperkalemia: for each kilogram of crushed muscle, between 100 to 150 mEq of K can be released into the extracellular fluid.

Hypoaldosteronism can also lead to hyperkalemia.

Three components to treatment

1) Antagonism of membrane effects of potassium: Calcium administration

Antagonizes membrane depolarization induced by hyerkalemia. Indicated when EKG shows widened QRS or loss of P waves but no peaked T waves alone. Begins immediately but is short lived. Ca can be administered as CaCl2 (three times the Ca concentration in Ca gluconate; must be administered via central line), or Ca gluconate (may be administered via peripheral IV line). Infuse IV over 2 to 3 minutes under constant EKG monitoring; can be repeated if EKG changes persist after 5 minutes.

2) Intracellular shift of potassium

  • Insulin and glucose: Induces K decrease of 0.5 to 1.5 mEq/L; begins to act in ~15 minutes and peaks at 60 minutes, wears off in 1 to 3 hours.

  • Sodium bicarbonate: Use is controversial. Effectiveness is uncertain, may actually induce further shift of K into the extracellular space.

  • Beta-adrenergic agonists: Drive K intracellularly by stimulating Na/K ATPase. Peak effect within 30 minutes and 90 minutes with nebulization.

3) Removal of excess potassium

Diuretics: Loop diuretics more powerful and rapidly effective than thiazide diuretics. Modest effect on K levels in the acute setting, especially in patients with CKD.

Cation-exchange resins: Sodium polystyrene sulfonate (SPS)

Can be used orally or—less effectively—as retention enema. Dose usually 1g/kg/dose in children and 15 to 30g in adults; may be repeated every 4 to 6 hours. Effect may take 4 to 24 hours. Effectiveness is controversial, especially among patients with end stage renal disease.

Ischemic colitis and colonic mucosal necrosis are important complications attributed to SPS use or concomitant administration of high-concentration sorbitol as a laxative. Necrosis commoner when sorbitol is used in high concentration 70% but also reported when a 33% sorbitol concentration was used. Use of the resin without sorbitolis preferable to decrease risk of intestinal necrosis. FDA released a recommendation in 2009 that SPS should be used without sorbitol. SPS plus sorbitol should not be used perioperatively as it further increases the risk of intestinal mucosal ischemia. Avoid repeated/chronic use; address the reason for persistent hyperkalemia.

Dialysis: In the alternative between SPS and dialysis, dialysis should be preferred if patient already on dialysis or in patients with severe degree of hyperkalemia and renal dysfunction unlikely to rapidly respond to conservative measures. Intermittent hemodialysis is the most effective and rapid treatment for persistent, life-threatening hyperkalemia.

Hemodialysis may remove up to 25 to 50 mEq per hour. K dialysate bath concentration: Avoid zero K bath, use 1 mEq/L concentrations with great caution and under continuous EKG monitoring. See Table III.

Table III.
Predialysis Serum K Dialysate K Special considerations
<4.0 4.0
4.0 to 4.5 3.5
4.6 to 5.5 3.0 2.0 if rapid interdialytic increase expected
>5.5 but <8.0 2.0 Increase to 2.5 or 3 in patients at risk of arrhythmia or on digitalis

In patients with severe hyperkalemia greater than8.0 mEq/L, a dialysate concentration of 1.0 can be used for a short period (ie, 1 hour) to rapidly decrease K levels; switch to 2.0 K bath as soon as serum K levels reach 6 to 7 mEq/L. Zero K bath is not recommended due to inappropriate risk of severe arrhythmia. Avoid excessively rapid correction of hyperkalemia to decrease risk of arrhythmia; keep patients under continuous EKG monitoring.

Potassium rebound: Immediate post-dialysis measurements of serum K are misleadingly low. If K rebounds, consider continuous renal replacement therapies, which are slower for initial correction of hyperkalemia.

Management of Hypomagnesemia

Severe symptomatic hypomagnesemia must be emergently treated to rise to Mg greater than 1 mg/dL. Total body Mg stores may not be reflected by serum Mg levels and may need prolonged treatment for complete replacement. As serum Mg rises with treatment, significant ongoing renal loss may require additional treatment.

Serum Mg levels are the main regulator of renal Mg reabsorption in the loop of Henle: abrupt elevation in serum Mg will decrease Mg reabsorption and up to 50% of the infused dose may be lost in the urine. Simultaneous K depletion must by replenished.

Severe hypomagnesemia

50 mEq IV Mg slowly infused over 8 to 24 hours: 16 to 24mL of 50% magnesium sulphate (64 to 96 mEq) in 500 mL 5% dextrose over 6 to 8 hours; may repeat every 12 hours. In renal failure decrease dose to one half.

Mild to moderate hypomagnesemia

Avoid factors inducing Mg loss. Oral elemental Mg 10 to 20 mg/kg/dose up to 250 to 500mg/dose given 3 to 4 times per day to avoid diarrhea. Slow release preparations preferable: Slow Mag contains magnesium chloride and Mag-Tab SR contains magnesium lactate. These preparations provide 5 to 7 mEq (2.5 to 3.5 mM or 60 to 84 mg) of elemental Mg per tablet. Patients with thiazide- or loop diuretic -induced hypomagnesemia may benefit from a K-sparing diuretic such as amiloride.

Patients with chronic kidney disease

Avoid Mg supplementation in patients with renal dysfunction unless magnesium-deplete (serum Mg less than 1 mg/dL). Closely monitor Mg levels as Mg is repleted. For patients with creatinine clearance 15 to 30 mL/min (CKD4) should receive one half the usual dose of Mg. Patients on chronic dialysis are rarely Mg depleted.

Management of Hypermagnesemia

Magnesium overload should be avoided by limiting the intake of Mg-containing medications especially in patients with reduced kidney function.

Normal renal function: Supportive treatment, hydration, loop diuretics

Severe hypermagnesemia: Symptoms can be acutely reversed with intravenous Ca administration 100 to 200mg IV infused over 5 to 10 minutes. If levels are elevated in the face of renal dysfunction and hypermagnesemia is symptomatic, consider hemodialysis.

Management of Hypocalcemia

Management depends on the severity of symptoms, which depends on absolute concentration of ionized calcium and rate of decrease. In patients with acute symptomatic hypocalcemia, intravenous Ca gluconate is the preferred therapy. Severity indicators include carpopedal spasm, tetany, seizures, prolonged QT interval and acute decrease less than 7.5 mg/dL (1.9 mM). In patients with chronic hypocalcemia, oral calcium supplements and vitamin D supplements are indicated.

Intravenous calcium

Initial infusion of Ca gluconate 1 to 2g [equivalent to 90-180mg elemental Ca] in 50 mL of 5% dextrose in water infused over 10 to 20 minutes. Avoid faster infusion rate because of risk of severe cardiac dysfunction or arrest. This dose will be effective for 1 to 2 hours; initial injection should be followed by continuous infusion 10% Ca gluconate (90mg elemental Ca/10 mL) or 10% CaCl (270mg elemental Ca/10 mL) can be used to prepare the solution.

Ca gluconate is safer for peripheral infusion as it is associated with lesser risk of tissue necrosis if extravasation occurs: Intravenous solution 1mg/mL (11g Ca gluconate in saline or 5% dextrose final volume 1000 mL). Typical infusion is rate 0.5 to 1.5 mg/kg/hour to maintain stable ionized calcium level. Avoid simultaneous infusion of phosphate or bicarbonate and—if needed—give via a separate line to avoid precipitation of calcium phosphate or carbonate. Simultaneous infusion of active vitamin D such as calcitriol 0.25 to 0.5mcg twice daily is usually necessary.

Concurrent hypomagnesemia

Hypomagnesemia can lead to resistant hypocalcemia by decreasing PTH secretion and causing resistance to PTH effects. If serum Mg is initially low, administer 2g (16 mEq) of Mg sulphate as a 10% solution over 10 to 20 minutes followed by 1g (8 mEq) in 100 mL fluid per hour. Continue Mg repletion until serum Mg level is greater than 0.8 mEq/L (1mg/dL). Monitor EKG continuously and renal dysfunction: patients with renal failure are at high risk of Mg toxicity.

Oral calcium

Adequate for milder degrees of acute hypocalcemia (serum ionized Ca above 3 to 3.2 mg/dL [0.8 mM]) or for chronic hypocalcemia. Initial treatment 1500 to 2000mg elemental Ca as calcium carbonate or calcium citrate daily in divided doses.

Vitamin D metabolites

The dose varies greatly between individuals and clinical situations. Patients with hypoparathyroidism should receive 1,25(HO)2D (calcitriol), initial dose 0.25 to 0.5mcg twice daily. Monitor serum Ca and urinary Ca excretion. Hypercalciuria (Ca excretion >300 mg/day, >4 mg/kg/day) may occur in the absence of hypercalcemia, especially in patients with hypoparathyroidism. If hypercalciuria develops, calcitriol discontinuation will resolve the problem; if persistent, a short course of oral glucocorticoids will be effective.


Most patients with hypoparathyroidism require lifelong Ca and vitamin D supplementation. Initial dose, Ca 1.0 to 1.5g elemental calcium/day in divided doses. Calcium carbonate is inexpensive and widely available. Calcium citrate may be easier to absorb for elderly patients with hypochlorhydria. Calcitriol 0.25 to 0.5mcg twice daily is usually necessary; dose can be increased up to 2.0mcg/day.

Prevent hypercalciuria: patients with hypothyroidism reabsorb Ca less efficiently and tend to develop hypercalciuria, with associated risks of nephrolithiasis and nephrocalcinosis. Thiazide diuretics 25 to 100mg/day may prevent hypercalciuria; sodium restriction potentiates the effect and K supplementation may be necessary. Recombinant PTH, now only approved for the treatment of osteoporosis, may be available in the future to correct hypoparathyroidism.

Hypoparathyroidism in pregnancy and during lactation is an especially important situation, especially in the third trimester of pregnancy or after delivery, a problem in lactating mothers. During pregnancy, serum levels of 1,25(OH)2D double but serum PTH concentrations remain normal, indicating that other mechanisms, poorly established and likely including PTHrP, stimulate kidney 1-alpha hydroxylase. There is disagreement whether hypoparathyroid mothers experience decreased calcitriol requirements during late pregnancy, but lactating mothers generally show decreased calcitriol requirements.

Measure serum Ca frequently during late pregnancy and lactation in hypoparathyroid women to avoid hypercalcemia; decrease calcitriol supplements accordingly. Calcitriol requirements will return to antepartum levels upon cessation of pregnancy.

Vitamin D deficiency: Usual replacement dose is ergocalciferol 50,000units weekly for 6 to 8 weeks.

Chronic kidney disease

Severe hypocalcemia is uncommon. Calcium supplements are used to both replace Ca and to bind P in the intestine. The majority of patients receive calcitriol to compensate for decreased 1-alpha hydroxylase activity in the insufficient kidney. Calcimimetics such as cinacalcet are agonists of the parathyroid calcium receptor used to manage secondary hyperparathyroidism. These medications may induce hypocalcemia; close Ca monitoring is mandatory.

Management of Hypercalcemia

The degree of hypercalcemia and the rate of increase determine the need for treatment and the choice of measures to correct it. Acute onset of hypercalcemia is worse tolerated than chronic hypercalcemia: symptomatic hypercalcemia requires aggressive treatment. Patients with serum Ca greater than14 mg/dL require treatment regardless of symptoms.

Mild hypercalcemia

Asymptomatic or serum Ca less than 12 mg/dL (3 mM), no immediate treatment required. Avoid Ca supplements and medications such as lithium or thiazides, which can exacerbate hypercalcemia, avoid immobility and ensure adequate hydration.

Moderate hypercalcemia

Asymptomatic or mildly symptomatic with chronic moderate hypercalcemia (serum Ca 12 to 14 mg/dL [3 to 3.5 mM]. Same precautions as mild hypercalcemia. Severely symptomatic patients must be treated as those with severe hypercalcemia. Typically treatment consists of biphosphonates and saline hydration.

Severe hypercalcemia (Serum Ca greater than 14 mg/dL [3.5 mM])

Volume expansion with isotonic saline 200 to 300 mL/h, adjust rate to maintain diuresis 100 to 200 mL/h. If congestive heart failure or renal failure is not present, avoid diuretics: they are ineffective and other medications such as biphosphonates will address the mechanism of hypercalcemia.

Salmon calcitonin (CT) 4units/kg and repeat serum Ca 8 to 12 hours later: if Ca decreases, patient is CT sensitive and the CT can be repeated every 12 hours 4 to 8 units/kg. Concurrent administration of biphosphonates: zoledronic acid (4mg IV over 15 minutes) or pamidronate (60 to 90mg infused over 2 hours). Zoledronic acid is more powerful than pamidronate. CT plus saline should decrease serum Ca within 12 to 24 hours; the biphosphonate will be effective within 2 to 4 days.

Treat underlying disease such as malignancy. Consider hemodialysis in the severely symptomatic patient with serum Ca 18 to 20 mg/dL (4.5 to 5 mM) and neurologic symptoms but hemodynamically stable.

Additional measures

Primary hyperparathyroidism: Manage with calcimimetics or adenoma resection

Lymphoma, sarcoidosis or other granulomatous diseases have hypercalcemia due to overproduction of calcitriol causing elevated intestinal absorption of Ca: main measures include low Ca diet, corticosteroids to inhibit 1,25(OH)2D synthesis, and treatment of the underlying disease. Excess calcitriol dose: effects only lasts 1 to 2 days due to short half-life and resolves spontaneously. Consider hydration or IV saline. or vitamin D intoxication will need more prolonged treatment and pamidronate may be necessary. Familial hypocalciuric hypercalcemia should not be treated.

Other considerations

Loop diuretics have fallen out of favor as they can induce volume contraction, hypokalemia, hypomagnesemia and metabolic alkalosis. Calcitonin is only effective within the first 24 to 48 hours. Biphosphonates have potential renal toxicity and should be used with caution in patients with severely impaired renal function (serum creatinine >4.5 mg/dL). See Table IV. Management of hypercalcemia

Table IV.
Isotonic saline hydration Intravascular volume expansionIncrease ECa Hours During infusion
Loop diuretics Decreased RCa TALH Hours During therapy
Calcitonin Inhibit bone reabsorption Increases ECa 4-6 h 48 h
Biphosphonates Inhibit bone reabsorption decreasing osteoclast 24-72 h 2-4 weeks
Glucocorticoids Decrease intestinal absorption Ca Decrease 1,25(OH)2D production in granuloma 2-5 days Days to weeks
Gallium nitrate Inhibits osteoclasts 3-5 days 2 weeks
Calcimimetics CaSR agonist reduces PTH secretion 2-3 days During therapy
Dialysis Low Ca dialysate Hours During therapy

ECa=Calcium excretion; RCa=Calcium reabsorption; TALH=Thick ascending loop of Henle; CaSR=Calcium-sensing receptor; PTH=Parathyroid hormone.

From: Shane E, Dinaz I. Hypercalcemia: pathogenesis, clinical manifestations, differential diagnosis and management. In: Primer on the metabolic bone diseases and disorders of mineral metabolism. 6th Ed. American Society of Bone and Mineral Research; 2006. p 179.



Plasma K less than 3.5 mEq/L: For each 1 mEq/L decrease in plasma K below 3 mEq/L, there is a corresponding loss of 200 to 400 mEq K in a 70 kg adult. Hypokalemia below 3.0 mEq/L is considered moderate to severe.


  • Decreased intake below 1.5 mEq/Kg/day

  • Kidney is unable to decrease K excretion below 5 to 25 mEq/day

Usual settings

Diuretic therapy

Laxative abuse

High-carbohydrate diets

Potassium- free IV fluids


K redistribution

Stress causing elevated catecholamine levels

Surreptitious use of simpathomimetics such as pseudoephedrine

Excessive coffee consumption

Head trauma

Insulin administration, carbohydrate loads

Marked leukocytosis in acute leukemia may cause pseudohypokalemia due to intracellular intake.

Hypokalemic periodic paralysis: Rare autosomal dominant genetic disorder of muscle ion channels, causing sudden muscle paralysis precipitated by exercise, stress or carbohydrate load. It is frequently associated with thyrotoxicosis. There is a danger of rebound hyperkalemia after K replenishment, because intracellular K stores are normal and there is no total body K depletion.

Barium intoxication:Present in rodenticides. Barium inhibits K channels. Treatment consists of K administration and barium removal by hemodialysis.


Increased gastrointestinal loss

Vomiting: gastric secretion losses plus urinary losses increased by elevated serum bicarbonate levels and greater sodium bicarbonate delivery to the distal nephron, and secondary hyperaldosteronism induced by volume-contraction. Urine shows inappropriate K losses and very low (<10 mEq/L) Cl concentration.

Diarrhea: concurrent bicarbonate and K loss causing hyperchloremic metabolic acidosis and hypokalemia.

Severe in cases of large fecal loss: villous adenoma or VIP secreting tumors (VIPomas), severe infectious diarrhea.

Increased urinary loss

Two main factors that produce this are increased aldosterone effects and increased distal tubular fluid delivery. Diuretics increase K urinary loss owing to hyperaldosteronism or increased distal delivery of water and sodium. Diuretics act proximal to the site of tubular K secretion and induce delivery of greater water and salt load, leading to increased distal Na/K exchange. Thiazides cause more hypokalemia than loop diuretics. Loop diuretic-induced hypercalciuria limits the electrochemical gradient for K secretion.

Polyuria is occasionally seen in diabetes insipidus.

Metabolic alkalosis and volume contraction:

Vomiting induces volume contraction, hyperaldosteronism and increased excretion of potassium bicarbonate.

Metabolic acidosis

Diabetic ketoacidosis and excretion of nonreabsorbable ketoacid anions

Renal tubular acidosis type I (distal) and type II (proximal)

Hypomagnesemia induces increased urinary loss of K by unknown mechanisms. Hypokalemia cannot be corrected until the Mg deficit is corrected.


Primary: congenital or acquired. Clinical presentation includes hypertension, metabolic alkalosis and moderate hypokalemia worsened by thiazide diuretics.

Secondary hyperaldosteronism is due to increased renin levels caused by renal artery stenosis and edematous states such as congestive heart failure, nephrotic syndrome and liver cirrhosis. Less common causes include amphotericin B tubular toxicity and cisplatinum tubular toxicity. It is also associated with Mg depletion. Hypomagnesemia has inhibitory effects on Na/K ATPase and is refractory to K administration unless Mg is concurrently replenished.

Rare causes of hypokalemia

Syndrome of apparent mineralocorticoid excess, a recessive mutation in 11β-hydroxysteroid dehydrogenase 2 gene causes delayed inactivation of cortisol, causing hypertension, hypokalemia and metabolic alkalosis.

Bartter syndrome, an autosomal recessive genetic disorder with antenatal presentation or insidious onset during the first 2 years of life. It is characterized by hypokalemic alkalosis, hyperreninemia and hyperaldosteronemia, normotension, polyuria and polydipsia and stunted growth. There are five variants affecting different ion channels.

Gitelman syndrome, an autosomal recessive mutation in the gene encoding the NCCT channel in the distal tubule, induces Mg wasting and reduced Ca excretion similar to that caused by thiazide therapy. It presents in later childhood. Mild to moderate hypokalemic alkalosis, hypocalciuria and hypomagnesemia, salt wasting and polyuria due to impaired water reabsorption are common.

Liddle’s syndrome, an autosomal dominant gain of functional mutation of ENaC, the amiloride-sensitive Na channel on the connecting and cortical collecting duct. It is characterized by the triad of hypertension, hypokalemia and metabolic alkalosis in a young patient. There is also decreased urinary excretion of aldosterone. Genetic testing is indicated. Therapy consists of K-sparing diuretics to block Na channel. Spironolactone is ineffective.


Defined as K greater than 5.5 mEq/L. It is associated with significant mortality risk and its pathophysiology is usually multifactorial, chiefly reduced renal function and drugs.


Potassium redistribution

  • Pseudohyperkalemia: artificial increase in serum K after the blood is collected.

  • Hereditary spherocytosis and familial pseudohyperkalemia with increased temperature-dependent leakage of K out of red blood cells.

  • Severe leukocytosis or thrombocytosis such as in leukemia or myeloproliferative disease. With thrombocytosis, measured K rises by 0.15 mEq/L for every 100,000 per mm3 rise in platelet count.

Metabolic acidosis

  • Rhabdomyolysis with severe K translocation

  • Tumor lysis syndrome induced by chemotherapy

  • Plasma hypertonicity: mannitol treatment, severe hyperglycemia may induce K translocation due to transmembrane “solvent drag”

β2-blockade: Induced by non-selective β-blockers such as propranolol or alpha-beta blockers such as labetalol; avoidable by β1-selective blockers such as atenolol or metoprolol.

Exercise: Induced by delayed reuptake of K after membrane depolarization and open membrane K channels due to decline in intracellular ATP.

Rare causes:

  • Bufadienolide intoxication. Contact with skin and venom glands from
    Bufo marinus toad or ingestion of aphrodisiacs containing the toxin. May require treatment with digoxin-specific Fab fragment.

  • Fluoride intoxication: Succinylcholine depolarizes cell membranes and can result in transient hyperkalemia. At risk: patients with myopathies or rhabdomyolysis, ICU immobilization, thermal trauma.

  • Arginine hydrochloride: Metabolized to HCl, the entry of cationic arginine into cells obligates K exit to maintain electroneutrality.

  • Increased potassium intake

  • Blood transfusion: Prolonged cold storage of blood and rapid infusion increases risk

  • KCl supplementation

  • Reduced potassium excretion

  • Renal failure: Decreased glomerular filtration rate, decreased distal delivery of tubular fluid


Non-steroidal anti-inflammatory medications (NSAIDs)

  • Reduced prostaglandin production limits renin secretion

  • Reduced prostaglandins inhibit BK/maxi-K channel

  • Reduced glomerular filtration rate and Na/K exchange

Angiotensin converting enzyme Inhibitors (ACEI) and angiotensin receptor blockers (ARBs)

  • Decreased aldosterone secretion

  • Decreased glomerular filtration rate and renal blood flow

  • Potassium-sparing diuretics

  • Blockade of apical cell ENaC channels

  • Competitive blockade of aldosterone receptor: spironolactones and eplerenone

Trimethoprim and pentamidine: Block ENaC channels


  • Reduces aldosterone synthesis

  • Reduces response to angiotensin II by zona glomerulosa in adrenal glands

Calcineurin inhibitors:Cyclosporine can cause hyporeninemic hypoaldosteronism and interfere with the effect of aldosterone on K-secreting cells in the cortical collecting duct; digitalis overdose, due to dose-related Na/K ATPase pump inhibition; and hypoaldosteronism: low serum aldosterone, high renin level.

Autoimmune disease

Infection: HIV infected patients with cytomegalovirus (CMV) or Mycobacterium avium Intracellulare-induced adrenalitis.


Hyporeninemic hypoaldosteronism and type IV renal tubular acidosis: Low renin, low or normal aldosterone and normal cortisol levels. Common in older (50- to 70-year-old) patients with diabetic nephropathy or chronic interstitial nephritis and mild to moderate chronic renal failure. Common in obstructive uropathy and in sickle cell disease causing medullary injury.

Uncommon causes: Congenital adrenal hyperplasia: two situations:

  • CYP11B2 (Aldosterone synthase) deficiency: high renin, low aldosterone, normal cortisol level

  • CYP21A2 (21-hydroxylase), CYP17 (17-hydroxylase) or 3ß-hydroxysteroid dehydrogenase deficiency cause cortisol secretion deficiency and virilization due to increased androgen synthesis

Pseudohypoaldosteronism type I: Genetically determined tubular aldosterone hyporesponsiveness.

High renin and aldosterone levels

Pseudohypoaldosteronism type II: Gordon’s syndrome. Hypertension, hyperkalemia, metabolic acidosis, hypercalciuria and low bone density. Normal renal function and low renin/aldosterone concentrations. Due to genetically determined gain-of-function in thiazide-sensitive Na-Cl co-transporter

Ureterojejunostomy induced by reabsorption of urinary K by the jejunum.


Diagnose and correct underlying cause. Always measure and replace Mg if low to facilitate treatment: hypomagnesemic patients can be resistant to correction of hypokalemia and have malignant arrhythmias such as Torsade des Pointes in patients susceptible such as those with prolonged QT interval.

Prevent life-threatening conditions: Rapid drop of K to less than 2.5 mEq/L and/or cardiac arrhythmias call for urgent replacement.

Replete K deficit. Rule of thumb: in the absence of redistribution, K drops ~0.27 mEq/L for every 100 mEq K loss. In chronic hypokalemia, a K deficit of 200 to 400 mEq is required to lower serum K by 1 mEq/L, but those are only gross estimates: close monitoring is essential.

Supplementation is recommended for Kless than 3 mEq/L. Potassium chloride is the preferred preparation because it simultaneously replenishes chloride lost in vomiting or diuretic effects. Chloride deficiency maintains and worsens concurrent metabolic alkalosis.

Oral supplementation: Enrich K in diet. K in foodstuffs is only 40% retained. Prescribe KCl or K phosphate if hypophosphatemia present. Cl repletion is important to concurrently correct hypochloremic metabolic alkalosis if present; usual dose is 20 to 80 mEq/day in divided 2 to 4 doses in mild-to-moderate hypokalemia (3.0-3.4mEq/L). Monitor K levels as K levels will fall back within a few hours due to intracellular redistribution.

Intravenous administration: Indicated in severe hypokalemia (<3.4 mEq/L) or symptomatic (such as arrhythmia or rhabdomyolysis). Limited to patients unable to use enteral route or patient with severe signs or symptoms. Administer in saline solution rather than dextrose as dextrose will enhance intracellular entry of K. Usual infusion rate 10mEq/hour, maximum rate 10 to 20mEq/hour in life-threatening situations, under continuous clinical and EKG monitoring. Risk of arrhythmia and respiratory depression, paralysis

Address concurrent causes such as diuretic effects, high Na intake. Aggressive K repletion is usually limited to situations with severe K depletion such as diabetic ketoacidosis or hyperosmolar non-ketotic hyperglycemia, where patients have substantial urinary losses of K. In these situations, postpone initiation of insulin therapy until serum K greater than 3 to 3.5 mEq/L


Hyperkalemia may occur in the context of excess total body K such as in patients with renal failure, excess K administration or effects of ACE inhibitors. In those cases, removal of excess K is the main goal of treatment

Hyperkalemia may occur due to redistribution in patients with normal total body K stores such as in hyperkalemic periodic paralysis.

Hyperkalemia may occur in patients with depleted total K stores such as diabetic ketoacidosis or hyperosmolar hyperglycemia. In those cases, hyperkalemia may be followed by severe hypokalemia requiring K replacement.

Avoid fasting, especially in patients with end-stage renal disease because low insulin levels may promote hyperkalemia. Nondiabetic dialysis patients awaiting surgery should receive IV fluids containing glucose, and diabetic dialysis patients should receive a combination of glucose and low-dose insulin.

Address reversible causes:

  • Relieve urinary obstruction

  • Correct hypovolemia

  • Discontinue NSAIDs and inhibitors of the renin-aldosterone system

Emergency treatment if:

  • Symptomatic hyperkalemia, muscle weakness, paralysis

  • EKG changes

  • K level more than 6 mEq/L



Decreased dietary intake

  • Starvation

  • Protein-calorie malnutrition

  • Total parenteral nutrition

  • Decreased intestinal absorption: Chronic diarrhea, malabsorption syndromes such as celiac syndrome, short intestine, steatorrhea

Hypomagnesemia and secondary hypocalcemia

Tubular renal disorders

  • Gitelman and Bartter syndromes

  • Autosomal dominant hypoparathyroidism

  • Familial hypomagnesemia with hypercalciuria and nephrocalcinosis isolates and dominant and recessive hypomagnesemia

  • Mitochondrial hypomagnesemia

Secondary renal Mg wasting

  • Diabetes, DKA

  • Postobstructive diuresis

  • Volume expansion, hypoaldosteronism

  • Drugs: Diuretics except K-sparing diuretics, cistplatin, amphotericin, cyclosporin, tacrolimus, aminoglycosides



Hypermagnesemia is due to either decreased glomerular filtration rate or increased Mg load.

Renal failure

  • Unusual until glomerular filtration rate decreases to less than 30 mL/min

  • Most common in renal failure patients subject to Mg load: avoid Mg-containing medications such as antacids and enemas

Excess Mg load

  • Large accidental or voluntary overdose

  • Mg retention among patients with intestinal obstruction inflammation and perforation causing rapid Mg absorption

  • Therapeutic hypermagnesemia in pre-eclampsia, when serum levels reach 6 to 8 mg/dL (5-7 mEq/L, 2.5-3.5 mM)

  • Maternal hypocalcemia and hyperkalemia, and fetal hypermagnesemia possible

Asymptomatic hypermagnesemia is described in patients treated for aneurysmal subarachnoid hemorrhage.

Calcium disorders
1. Hypocalcemia
  • Defined as total Ca level <8.8 mg/dl in adults, ionized Ca <4.9 mg/dl (1.12 mM, 2.24 mEq/L)

  • Rule out ‘pseudohypocalcemia’ due to hypoalbuminemia. Gadolinium-based agents gadodiamide and gadoversetamide interfere with the colorimetric assay and cause pseudohypocalcemia

  • Ionized Ca should be measured directly rather than ‘calculated’

  • Phosphorus levels usually good clues to the mechanism of hypocalcemia. Low P in vitamin D dysfunction or depletion (secondary hyperparathyroidism); high P in renal failure (secondary hypoparathyroidism) or primary hypoparathyroidism

  • Most common causes of hypocalcemia include autoimmune hypoparathyroidism, postsurgical hypoparathyroidism and vitamin D deficiency

Causes of hypocalcemia


  • Congenital hypoparathyroidism: DiGeorge syndrome, maternal hypoparathyroidism in neonates, Ca receptor inactivating mutations.

  • Acquired hypoparathyroidism: Autoimmune, surgical removal or radiation damage of the thyroid and parathyroid glands, hypomagnesemia, phosphorus load

  • Endogenous: Tumor lysis syndrome, rhabdomyolysis; massive tissue breakdown releases intracellular P leading to precipitation of Ca in soft tissues and hypocalcemia.

Renal failure: Exogenous, phosphorous–containing enemas, high P formulas


Vitamin D deficiency

  • Lack of sun or dietary

  • Hypocalcemia, elevated alkaline phosphatase and PTH

  • Malabsorption syndromes: hepatobiliary disease, pancreatitis, Crohn’s disease and celiac syndrome

  • Renal failure decreasing 1,25(OH)2D production

  • Increased metabolism: Phenytoin and phenobarbital increase P450 inactivation of vitamin D.

  • Vitamin D-dependent rickets type 1 (VDDR 1)

  • Resistance to vitamin D: Type 2 vitamin D rickets (VDDR 2)

  • Deposition of Ca and P in tissues

  • Hungry bone syndrome post-parathyroidectomy


Sepsis, critical illness including toxic shock syndrome

  • Incidence 80% to 90%

  • Associated with hypoparathyroidism and PTH resistance and reduced calcitriol production

  • Hypocalcemia a poor prognostic index


  • Biphosphonates used to treat hypercalcemia due to Paget’s disease, immobility or bone metastasis

  • Cinacalcet inhibits CaSR in the parathyroid gland and may cause severe hypocalcemia (5% incidence)

  • Cisplatin commonly causes hypocalcemia

  • Combination 5-fluorouracil and leucovorin may cause hypocalcemia in 65% of patients.

  • Foscarnet used to treat CMV and herpes infection in HIV patients, complexes with Ca and may cause hypocalcemia.

  • Fluoride poisoning

Pancreatitis: Osteoblastic cancer metastasis from breast or prostate cancer may induce hypocalcemia and secondary hyperparathyroidism.

Altered calcium-citrate ratio: citrate anticoagulation in dialysis, plasmapheresis or ECMO, massive blood product transfusion.

Hypoparathyroidism in pregnancy and during lactation is an important situation, especially in the third trimester of pregnancy or, after delivery, a problem in lactating mothers. During pregnancy serum levels of 1,25(OH)2D double but serum PTH concentrations remain normal, indicating that other mechanisms, poorly established and likely including PTHrP, stimulate kidney 1-alpha hydroxylase.

There is disagreement whether hypoparathyroid mothers experience decreased calcitriol requirements during late pregnancy, but lactating mothers generally show decreased calcitriol requirements. Measure serum Ca frequently during late pregnancy and lactation in hypoparathyroid women to avoid hypercalcemia; decrease calcitriol supplements accordingly. Calcitriol requirements will return to antepartum levels upon cessation of pregnancy.

Magnesium depletion

Mg depletion causes hypoparathyroidism by decreasing PTH secretion and inducing PTH resistance when Mg levels <0.8 mEq/L (1 mg/dl or 0.4 mM). Malabsorption, chronic alcoholism and cisplatin therapy are the most common causes of magnesium depletion. Other uncommon causes include high dose thiazide treatment, prolonged parenteral nutrition and administration of aminoglycosides. Despite elevated PTH levels hypomagnesemic patients generally show hypophosphatemia, commonly due to malnutrition.

2. Hypercalcemia

Hypercalcemia is a relatively common problem. Greater than 90% of cases are due to either metastatic malignancy or hyperparathyroidism. Hypercalcemia occurs when entry of Ca into the circulation exceeds the excretion of calcium plus bone deposition. Hypercalcemia is commonly due to either accelerated bone reabsorption, excessive gastrointestinal absorption or decreased renal excretion of Ca. Frequently a combination of mechanisms are at play simultaneously.

Bone reabsorption

Primary hyperparathyroidism involves PTH-mediated activation of osteoclasts causing osteolysis plus increased intestinal absorption of Ca due to increased renal synthesis of 1,25(OH)2D. Ca levels may be mildly elevated or temporarily normal.

Patients with severe chronic renal disease and secondary hyperparathyroidism usually have normal to low serum Ca but may develop hypercalcemia with severe prolonged disease and a dynamic bone disease. Prolonged severe secondary hyperparathyroidism can lead from glandular hyperplasia to autonomous adenoma formation and overproduction of PTH.

After renal transplantation, hypercalcemia may develop due to tertiary hyperparathyroidism plus normalization in renal production of 1,25(OH)2D.


Ca levels greater than 13 mg/dL (3.25 mM) are most likely due to malignancy. The mechanism varies depending on the kind of cancer. Metastatic disease induces direct osteolysis. Multiple myeloma releases osteoclast activating factors. In non-metastatic solid cancers, the commonest mechanism is production of PTHrP. In lymphoma, hypercalcemia is due to extrarenal PTH-independent overproduction of calcitriol.

Thyrotoxicosis may cause moderate, generally asymptomatic, hypercalcemia in 15% to 20% of cases. Other causes include immobilization, Paget’s disease, and bed rest, administration of estrogen or tamoxifen to patients with breast cancer and extensive bone metastasis, and hypervitaminosis A and treatment with retinoic acid or trans- or cis-retinoic acid of certain tumors.

Calcium absorption

Calcium is absorbed in the duodenum and upper jejunum via passive and active mechanisms. In patients with a normal intake of Ca, active transport is quantitatively more important and is regulated by 1,25(HO)2D. Patients subject to Ca greater than 1 to 2 g/day may passively absorb substantial amounts of Ca.

Excessive Ca intake can rarely lead to hypercalcemia unless other mechanisms coexist:

  • Decreased renal excretion due to acute or chronic renal insufficiency. Patients with chronic kidney disease on large doses of oral Ca as a P binder plus simultaneous administration of calcitriol.

  • Excess vitamin D intake induces increased intestinal absorption of Ca plus, at high doses, bone reabsorption. Increased levels of 25HOD3 indicate either excessive ingestion of vitamin D or ergocalciferol, or excessive ingestion of calcidiol (25HOD3). Increased levels of 25(HO)2D indicate either excessive intake of calcitriol (PO or IV) or extrarenal production of 1,25(HO)D such as granulomatous disease including sarcoidosis or malignant lymphoma or (rarely) idiopathic endogenous overproduction of calcitriol.

  • Milk-alkali syndrome: Excessive consumption of milk or calcium carbonate causes hypercalcemia, metabolic alkalosis and renal failure.

  • Metabolic alkalosis potentiates hypercalcemia by increasing distal tubular Ca reabsorption. This is commonly seen in patients being treated for osteoporosis or gastric dyspepsia.

Other less common causes


  • Lithium therapy increases PTH secretion. Thiazide diuretics lower urinary Ca excretion.

  • Pheochromocytoma rarely presents with hypercalcemia either as part of the MEN2 syndrome or independently, likely due to tumor production of PTHrP.

  • Adrenal insufficiency: Addissonian crisis can be associated with hypercalcemia.

  • Cortisol reverses hypercalcemia

  • Theophylline toxicity; effects resolve with administration of β-adrenergic antagonists

Renal failure

Rhabdomyolysis and acute renal failure: In the diuretic (recovery) phase of AKI owing to rhabdomyolysis, hypercalcemia may develop because of mobilization of Ca previously deposited in injured muscle.

Contributing factors include secondary hyperparathyroidism due to renal failure, unexplained increased calcitriol levels, and correction of hyperphosphatemia as renal function improves. Similar mechanisms can be seen after renal transplantation.


  • Familial hypocalciuric hypercalcemia is an autosomal dominant disorder causing loss of function mutation in the CaSR in parathyroid cells and kidneys.

  • Metaphyseal chondrodysplasia associated with hyperfunction of the PTH receptor.

  • Congenital lactase deficiency causing hypercalciuria and nephrocalcinosis in neonates.

What's the evidence?

Mount, DB, Zandi-Nejad, K, Brenner, BM. “Disorders of potassium balance”. Brenner and Rector's the kidney. 2008. pp. 547

Rose, BD, Post, TW, Rose, BD, Post, TW. “Hypokalemia”. Clinical physiology of acid base and electrolyte disorders. 2001. pp. 836

Goilav, B, Trachtman, H, Feld, LG, Kaskel, FJ. “Disorders of potassium balance”. Fluid and electrolytes in pediatrics. 2009. pp. 67

Cerda, J, Tolwani, A, Warnock, D. “Critical care nephrology: Management of acid-base disorders with CRRT”. Kidney Int. vol. 82. 2012. pp. 9-18.

Agus, ZS, Massry, SG, Narins, RG. “Hypomagnesemia and hypermagnesemia”. Maxwell & Kleeman's clinical disorders of fluid and electrolyte metabolism. 1994. pp. 1099-119.

Reikes, S, Gonzalez, EA, Martin, KJ, DuBose, TD, Hamm, LL. “Abnormal calcium and magnesium metabolism”. Acid base and electrolyte disorders. 2002. pp. 453-487.

Pollack, MR, Yu, ASL, Brenner, BM. “Clinical disturbances of calcium, magnesium and phosphate metabolism”. Brenner and Rector's The kidney. vol. Vol 1. 2004. pp. 535-71.

McKay, CP, Feld, LG, Kaskel, FJ. Fluid and electrolytes in pediatrics. 2009. pp. 149

McKay, CP, Feld, LG, Kaskel, FJ. “Disorders of calcium metabolism”. Fluid and electrolytes in pediatrics. 2009. pp. 105

Shane, E, Dinaz, I. “Hypercalcemia: pathogenesis, clinical manifestations, differential diagnosis and management”. Primer on the metabolic bone diseases and disorders of mineral metabolism. 2006. pp. 179