Disorders of K, Mg, and Calcium balance

Table IV.

INTERVENTION	MODE OF ACTION	ONSET OF ACTION	DURATION OF ACTION
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

Pathophysiology

Hypokalemia

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.

Causes

• 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

Malnutrition

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.

Hypothermia

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.

Hyperaldosteronism

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.

Hyperkalemia

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.

Causes

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

Drugs

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

Heparin

• 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.

Medications

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.

Hypokalemia

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

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

Hypomagnesemia

Causes

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

Causes

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

Hyperphosphatemia

• 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

Hypophosphatemia

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

Other

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

Drugs

• 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.

Malignancy

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

Drugs

• 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.

Genetics

• 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?

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

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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

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