Chapter 1.

5 Disorders of Phosphate Metabolism 63

Hyperphosphatemia
■ Essentials of Diagnosis
• Serum inorganic phosphorous (Pi) concentration greater than
4.5 mg/dL.
• Occurs due to increased phosphorous intake, decreased renal
phosphorous excretion, or transcellular shifts of phosphorous
from cells into extracellular fluid space.
• Acute hyperphosphatemia can cause hypocalcemia and related
clinical manifestations including tetany, and sequelae of calcium-
phosphate salt deposition in kidneys, heart, blood vessels.
• Chronic hyperphosphatemia can result in tissue phosphate
deposition and secondary hyperparathyroidism (in patients with
chronic kidney disease).

■ Differential Diagnosis
• Decreased renal excretion: acute or chronic kidney disease, hypo-
parathyroidism, pseudohypoparathyroidism, tumoral calcinosis.
• Increased phosphorous intake: usually requires reduced renal
excretion, phosphate-containing laxatives and enemas, parenteral
nutrition, vitamin D toxicity.
• Release of phosphorous from cells: tumor lysis syndrome, rhab-
domyolysis, severe hemolytic anemia, acute leukemia, fulminant
hepatic necrosis.

■ Treatment
• Directed at the cause of the hyperphosphatemia.
• If occurring at reduced GFR, treatment should also include
decreased intake and use of oral phosphate binders.
• If severe, acute, and refractory to other treatments, then dialysis
may be required.
• Calcimimetics (cinacalcet) may be used in secondary hyperpara-
thyroidism of chronic kidney disease.

■ Pearl
Severe acute hyperphosphatemia can occur with use of sodium phos-
phate laxatives and enemas; and can cause severe acute hypocalcemia,
acute phosphate nephropathy, and death.

References
Markowitz GS, Perazella MA: Acute phosphate nephropathy. Kidney Int
2009;76:1027.
Molony DA, Stephens BW: Derangements in phosphate metabolism in chronic
kidney diseases/endstage renal disease: therapeutic considerations. Adv
Chronic Kidney Dis 2011;18:120.
64 Current Essentials: Nephrology & Hypertension

Hypophosphatemia
■ Essentials of Diagnosis
• Defined as a serum inorganic phosphate (Pi ) concentration <1.0 mg/
dL. Pi concentration 1.0–2.5 mg/dL is usually asymptomatic.
• Clinical manifestations include muscle weakness or paralysis,
bone disease, hemolysis, increased risk of infection depending on
severity and chronicity.
• Frequently encountered among alcoholic patients with other elec-
trolyte abnormalities and patients with nutritionally deficient
states such as anorexia nervosa and malabsorption.
• Can occur acutely in patients with acute respiratory alkalosis due
to intracellular shift of phosphate.
• Also occurs in association with severe illness, diabetic ketoaci-
dosis, sepsis, extensive burns.

■ Differential Diagnosis
• Decreased phosphorous intake or intestinal absorption: vitamin D
deficiency (with rickets in children and osteomalacia in adults),
vitamin D-resistant rickets, use of phosphate-binding antacids or
calcium supplements, intestinal disorders with malabsoption of
Pi and vitamin D, malnutrition, alcoholism.
• Increased renal phosphate excretion: primary hyperparathyroid-
ism, Fanconi syndrome (primary or drug/toxin related), alcohol-
ism, treatment of ketoacidosis, x-linked hypophosphatemic
rickets, autosomal dominant hypophosphatemic rickets, onco-
genic osteomalacia.
• Transcellular shifts of inorganic phosphate: respiratory alkalosis,
extensive burns, leukemia blast crisis, refeeding syndrome, insu-
lin administration.

■ Treatment
• Treat underlying cause.
• Mild hypophosphatemia can be treated with oral replacement (eg,
milk, other dairy products, sodium- and potassium phosphate salts).
• More severe hypophosphatemia should be treated with intrave-
nous sodium or potassium phosphate supplementation.

■ Pearl
Acute respiratory alkalosis can cause rapid development of profound
hypophosphatemia that will spontaneously correct when the respiratory
alkalosis resolves and does not generally require any specific treatment.

Reference
Amanzadeh J, Reilly RF Jr: Hypophosphatemia: an evidence-based approach to
its clinical consequences and management. Nat Clin Prac Nephrol 2006;2:136.
 Chapter 1.5 Disorders of Phosphate Metabolism 65

Hypophosphatemic Rickets
■ Essentials of Diagnosis
• Vitamin D-dependent (or resistant) rickets (VDDR) type I is due
to mutations in the renal 1-alpha hydroxylase gene with defi-
ciency of active vitamin D. Type II VDDR is due to defects in the
vitamin D receptor with resistance to the effects of vitamin D.
Both are autosomal recessive.
• X-linked hypophosphatemic rickets (XLHR) involves mutation
in the PHEX gene that encodes a peptidase that degrades phos-
phaturic factors (“phosphatonins”) such as FGF-23.
• Autosomal dominant hypophosphatemic rickets (ADHR) is due
to gain-of-function mutations in the gene encoding FGF-23 lead-
ing to its overexpression.

■ Differential Diagnosis
• VDDR I and II have hypocalcemia, elevation of alkaline phos-
phatase and PTH levels, and normal to mildly decreased levels of
25 (OH) vitamin D. 1,25 (OH)2 vitamin D is very low in VDDR I
and normal or increased in VDDR II. Bone disease is severe and
motor retardation, delayed growth, myopathy, and dental enamel
hypoplasia are usually present in VDDR I.
• XLHR and ADHR have phosphaturia and severe hypophospha-
temia with normal calcium and PTH levels. 25 (OH) vitamin D
levels are normal and 1,25 (OH)2 vitamin D levels are normal or
mildly decreased. XLHR is associated with delayed growth.
ADHR is associated with muscle weakness and often less sig-
nificant bone manifestations.

■ Treatment
• VDDR I requires large doses of vitamin D but can also be man-
aged with more physiologic doses of calcitriol. VDDR II is treated
with large doses of calcium supplementation.
• XLH and ADHR are treated with oral phosphorous replacement
and large doses of calcitriol.

■ Pearl
These disorders can usually be diagnosed on clinical grounds and with
testing of calcium, PTH, and 25 (OH) vitamin D levels so that testing
for 1,25 (OH)2 vitamin D is usually not necessary.

References
Alizadeh Naderi AS, Reilly RF: Hereditary disorders of renal phosphate wasting.
Nat Rev Nephrol 2010;6:657.
Tenenhouse HS, Murer H: Disorders of renal tubular phosphate transport. J Am
Soc Nephrol 2003;14:240.
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 1.6
Disorders of Magnesium Metabolism

Hypermagnesemia ........................................................................ 69
Hypomagnesemia ......................................................................... 70
Renal Magnesium Wasting ........................................................... 71

67
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 Chapter 1.6 Disorders of Magnesium Metabolism 69

Hypermagnesemia
■ Essentials of Diagnosis
• Serum magnesium concentration greater than 2.5 mg/dL (2.1 mEq/L).
• Patients are usually asymptomatic until the serum Mg exceeds
4–5 mg/dL; clinical manifestations at higher levels include:
o 5–7 mg/dL: hyporeflexia, nausea, vomiting, flushing.
o 7–12 mg/dL: loss of deep tendon reflexes, respiratory depression,
lethargy, hypotension, EKG changes (prolonged PR, QRS, and
QT intervals), hypocalcemia.
o More than 12 mg/dL: apnea, paralysis, coma, complete heart
block, asystole.

■ Differential Diagnosis
• Hypermagnesemia occurs primarily in patients with impaired
renal magnesium excretion capacity due to advanced CKD or
acute renal failure. These patients are vulnerable to severe and
potentially fatal hypermagnesemia when exposed to a high mag-
nesium load, which may be endogenous (eg, tumor lysis, rhabdo-
myolysis) or exogenous (eg, ingestion of Mg-containing laxatives
and antacids).
• Rarely, hypermagnesemia can develop in patients with normal renal
function; examples include treatment of preeclampsia with large
doses of MgSO4, massive oral ingestions, and chronic laxative abuse.
• Some disorders cause increased renal magnesium absorption,
including hypothyroidism, adrenal insufficiency, hyperparathy-
roidism, and familial hypocalciuric hypercalcemia.

■ Treatment
• Discontinue any source of exogenous magnesium.
• If severe cardiovascular, neurologic, or respiratory complications
are present, administer IV calcium chloride or calcium gluconate
to antagonize the effects of magnesium.
• In patients with normal renal function who are not volume over-
loaded, volume expansion may enhance renal magnesium excre-
tion; loop diuretics can further augment magnesuria.
• Patients with renal failure may require dialysis for Mg removal.

■ Pearl
It is important to monitor calcium levels when using loop diuretics to
treat hypermagnesemia, since these agents can cause hypercalciuria
and hypocalcemia, which in turn exacerbates the clinical effects of
hypermagnesemia.

Reference
Topf JM, Murray PT: Hypomagnesemia and hypermagnesemia. Rev Endocr
Metab Disord 2003;4(2):195.
70 Current Essentials: Nephrology & Hypertension

Hypomagnesemia
■ Essentials of Diagnosis
• Serum Mg concentration more than 1.5 mg/dL (1.3 mEq/L).
• May be asymptomatic, especially if mild and slowly developing.
• The clinical manifestations of severe hypomagnesemia include:.
o Cardiovascular: arrhythmias (eg, torsade de pointes, ventricu-
lar fibrillation), magnification of digitalis toxicity, EKG
changes (PR prolongation, QRS widening, T wave changes).
o Neuromuscular: muscle weakness, fasciculations and cramps,
tremor, Chvostek and Trousseau signs, tetany, coma, seizures.
o Electrolyte disturbances: hypocalcemia, hypokalemia.

■ Differential Diagnosis
• Renal Mg wasting: diagnosed by a 24-hour urinary Mg excretion
greater than 10–30 mg or fractional excretion of Mg greater than
2% in the setting of hypomagnesemia. Causes include polyuric
states, ECF volume expansion, acquired tubular dysfunction,
hereditary Mg-wasting disorders, medications (eg, diuretics,
cisplatin), hypercalcemia. See separate topic for more details.
• GI losses: diarrhea (particularly if associated with fat malabsorp-
tion), GI fistulas, small bowel resection, or bypass.
• Redistribution into the intracellular compartment: refeeding syn-
drome, insulin therapy, metabolic alkalosis.
• The etiology of hypomagnesemia is often multifactorial in alco-
holics and diabetics, particularly in the setting of DKA.
■ Treatment
• If hypomagnesemia is severe (< 1.2 mg/dL or 1.0 mEq/L) or
symptomatic, administer a 1–2 g bolus of parenteral magnesium
sulfate over 15 minutes, followed by a continuous infusion of
4–6 g MgSO4 per 24 hours. Repletion should continue for
1–2 days after serum Mg normalizes. These doses should be
reduced in patients with decreased renal function.
• Use oral magnesium salts (preferably sustained release formula-
tions) for asymptomatic patients or those who need maintenance
therapy due to chronic Mg losses.
• Potassium-sparing diuretics may be benefi cial if renal Mg
wasting persists despite high-dose oral replacement.
■ Pearl
Normomagnesemic Mg depletion should be suspected in patients at
risk for Mg depletion who have clinical features consistent with Mg
deficit (eg, hypokalemia, hypocalcemia).

Reference
Agus ZS: Hypomagnesemia. J Am Soc Nephrol 1999;10(7):1616.
 Chapter 1.6 Disorders of Magnesium Metabolism 71

Renal Magnesium Wasting

■ Essentials of Diagnosis
• Hypomagnesemia (serum Mg < 1.5 mg/dL or 1.3 mEq/L).
• Inappropriately high renal Mg excretion, as evidenced by either
of the following:
o 24-hour urine collection showing greater than 10–30 mg of
magnesium excreted.
o Fractional excretion of Mg (FEMg) greater than 2%. FEMg is
calculated as follows: (urine Mg × plasma Mg)/(0.7 × plasma Mg
× urine Cr) × 100.
■ Differential Diagnosis
• Medications:
o Loop and thiazide diuretics: frequent cause of renal Mg wasting.
o Cisplatin: causes Mg wasting in more than 50% of patients.
o Other drugs include aminoglycosides, cyclosporine, pentamidine,
amphotericin B.
• Sustained ECF volume expansion (causing increased urinary sodium
excretion, which in turn causes magnesium wasting): primary hyper-
aldosteronism, administration of large amounts of normal saline.
• Polyuric states: uncontrolled hyperglycemia with glucosuria,
post-ATN diuresis, postobstructive diuresis, polyuria after renal
transplantation.
• Other electrolyte disturbances: hypercalcemia, hypokalemia, and
phosphate depletion inhibit tubular Mg reabsorption.
• Inherited disorders of renal Mg handling (rare):
o Diseases affecting the thick ascending limb of the loop of
Henle (eg, Bartter syndrome): associated with hypercalciuria
and hypocalcemia, and sometimes with hypokalemia.
o Diseases affecting the distal convoluted tubule (eg, Gitelman
syndrome): associated with low or normal urinary calcium.
■ Treatment
• Correction of the cause of Mg wasting whenever possible.
• Mg repletion using parenteral Mg for severe or symptomatic
hypomagnesemia, and oral Mg for maintenance therapy in
patients with chronic losses (see section on Hypomagnesemia).
• Potassium-sparing diuretics (eg, spironolactone, amiloride) if
hypomagnesemia persists despite high-dose oral replacement.
■ Pearl
The finding of hypermagnesuria and hypocalciuria suggests impaired
distal convoluted tubule function.

Reference
Konrad M, Weber S: Recent advances in molecular genetics of hereditary
magnesium-losing disorders. J Am Soc Nephrol 2003;14:249.