CORE CURRICULUM IN NEPHROLOGY

Disorders of Calcium, Phosphorus, and Magnesium

Sharon M. Moe, MD

䡲 D2 and D3 are carried by D-binding

NORMAL PHYSIOLOGY
protein to liver and hydroxylated to
Calcium (Ca), phosphorus (P), and magne- 25(OH)D, which is then further hydroxy-
sium (Mg) homeostasis is controlled by serum lated by 1-␣ hydroxylase enzyme in
concentrations of the ion and regulating hor- kidney to 1,25(OH)2D (calcitriol)
mones that act on 3 target organs: bone, intestine, 䡲 Some 1-␣ hydroxylase occurs in extrare-
and kidney. nal locations
䡲 24-Hydroxylase also is present in kidney
Regulating Hormones
and catabolizes to 1,24,25(OH)3D, which
Parathyroid hormone (PTH) is inert, and converts 25(OH)D to
● Released in response to lowering of ionized 24,25(OH)2D, which may have an effect
Ca via Ca-sensing receptor inactivation on bone
(ionized Ca decreases PTH release) ● Regulation:
● Cleaved from pre-pro PTH to pro PTH to 䡲 1-␣ hydroxylase enzyme activity (and
PTH in gland, and then secreted and catabo- thus 1,25[OH]2D) is increased by low P,
lized to N-terminal (active) and C-terminal low Ca, low calcitriol, and increased
fragments. Most of the C-terminal frag- PTH as major regulators; estrogen, pro-
ments are inactive, but some C-terminal lactin, calcitonin, and growth hormone
fragments (sometimes called “7-84” frag- also increase activity
ments although true sequence is not known)
䡲 1-␣ hydroxylase enzyme activity is de-
may have antagonistic effects on bone via
creased by 1,25(OH)2D forming feed-
different receptors.
back loop for regulation
● Activity:
䡲 Increases Ca reabsorption (and decreases ● Activity:
P reabsorption) from kidney 䡲 Calcitriol acts on intestine to increase Ca
䡲 Increases bone resorption by multiple and P reabsorption
mechanisms 䡲 Calcitriol acts on bone to increase miner-
䡲 Indirectly increases intestinal absorption alization and enhance osteoclast activity
by enhancing conversion of 25(OH) vita- 䡲 Calcitriol acts on PTH gland to inhibit
min D to 1,25(OH) vitamin D PTH secretion
● Regulation: 䡲 Calcitriol acts on kidney to ensure ad-
䡲 Hypocalcemia stimulates PTH secretion equate supply of calcitriol if levels are
䡲 Calcitriol (1,25[OH]2D) inhibits PTH low and is degraded in the kidney;
secretion, and PTH increases conversion
of vitamin D to calcitriol, thereby com-
pleting feedback loop for regulation
䡲 Hyperphosphatemia stimulates PTH se-
From the Department of Medicine, Indiana University School
cretion of Medicine, and Roudebush VAMC, Indianapolis, IN.
䡲 Severe hypomagnesemia stimulates PTH Received July 13, 2004; accepted in revised form October
secretion 6, 2004.
Address reprint requests to Sharon M. Moe, MD, Associ-
Vitamin D ate Professor of Medicine, Associate Dean of Research
● Metabolism: Support, Indiana University School of Medicine, 1001 W.
䡲 Sources of vitamin D are diet (D2 ergocal- 10th Street, OPW 526, Indianapolis, IN 46202. E-mail:
[email protected]
ciferol) and skin via conversion of 7-de- © 2004 by the National Kidney Foundation, Inc.
hydrocholesterol by UV light to D3 0272-6386/04/4501-0026$30.00/0
(cholecalciferol) doi:10.1053/j.ajkd.2004.10.014

American Journal of Kidney Diseases, Vol 45, No 1 (January), 2005: pp 213–218 213
214 SHARON M. MOE

whether it effects Ca and/or P tubular ● Extracellular Mg can be measured as total

uptake/excretion is controversial Mg, of which 55% is free or ionized and
physiologically active, 15% bound to an-
Phosphatonins ions, and 30% bound to albumin; no test for
● A group of substances that appear to regulate ionized Mg available clinically
serum P levels in tumor-induced osteomala- ● Average dietary intake of 300 mg/d, two
cia, X-linked hypophosphatemic rickets, and thirds excreted in stool and one third in
autosomal dominant hypophosphatemic rick- urine
ets
● Includes fibroblast growth factor 23, frizzled Target Organs
related protein 4, and matrix extracellular
Intestine
phosphoglycoprotein
● Role in normal physiology of P not yet ● Ca absorption is both passive and active,
clear (if any) the latter calcitriol dependent
● P absorption is both passive and active, the
Balance latter calcitriol dependent
● Mg absorption is passive only and directly
Calcium related to dietary intake
● Total body stores of approximately 1,000 g:
99% in bone, 0.9% intracellular, and 0.1% Kidney
extracellular ● Calcium:
● Extracellular Ca can be measured as total 䡲 60% to 70% absorbed in proximal tubule
Ca, of which 50% is free or ionized and via paracellular uptake in concert with
physiologically active (and can be mea- salt/water uptake
sured), 10% bound to anions, and 40% 䡲 20% to 30% absorbed in thick ascending
bound to albumin limb of Henle via primarily paracellular
● Correct total serum Ca for low albumin uptake energized by luminal Na/K/2Cl
([(Normal albumin concentration ⫺ pa- transporter, and some transcellular up-
tient’s albumin concentration) ⫻ 0.8] ⫹ take, perhaps mediated by basolateral
patient’s Ca concentration) Ca-sensing receptor
● Average dietary intake 500 to 1,000 mg/d, 䡲 10% absorbed in distal tubule and is
two thirds excreted in stool and one third in active, against both electrical and chemi-
urine cal gradients via luminal Ca channels,
and basolateral Ca/adenosine triphos-
Phosphorus phatase and Ca/Na exchangers
● Total body stores of approximately 600 g: 䡲 Ca reabsorption increased by extracellu-
85% in bone, 14% intracellular, and 1% lar volume contraction, PTH, PTH-
extracellular related peptide (PTHrp), hypocalcemia
● Extracellular P bound to albumin and cat- ● Phosphorus:
ions but, unlike Ca, only measure physiolog- 䡲 85% in proximal tubule via transcellular
ically active P uptake by Na/P cotransporter; remainder
● Average dietary intake 900 to 1,400 mg/d, in distal segments
two thirds excreted in urine and one third in 䡲 Uptake stimulated by extracellular vol-
stool ume contraction and hypophosphatemia,
inhibited by PTH, PTHrp, loop diuretics
Magnesium ● Magnesium:
● Total body stores of approximately 25 g: 䡲 40% absorbed in proximal tubule via
66% in bone (not freely exchangeable), paracellular uptake in concert with salt/
33% intracellular, 1% extracellular water uptake
● Serum levels not reflective of total body 䡲 50% absorbed in thick ascending limb of
stores Henle via primarily paracellular uptake
CORE CURRICULUM IN NEPHROLOGY 215

energized by luminal Na/K/2Cl trans- ● Constipation

porter ● Abdominal pain
䡲 5% absorbed in distal tubule via active ● Decreased mentation
transport ● Lassitude
䡲 Renal tubular reabsorption increased by ● Thirst
extracellular volume contraction, hypo- ● Dehydration
magnesemia, and PTH ● Reduced urine flow
Bone ● Nocturia
● Polyuria
● Bone is dynamic and goes through cycles
of remodeling: activation, osteoclast resorp-
● Volume depletion
tion, osteoblasts fill in resorption pit with
unmineralized matrix (osteoid), and matrix Differential Diagnosis
is then mineralized, cells undergo apoptosis
except some osteoblasts that become osteo- By prevalence:
cytes or lining cells
● Primary hyperparathyroidism (55%)
● Primary cells are osteoblasts (build new
bone) that derive from marrow stromal
● Malignancy (35%)
cells, osteoclasts (resorb bone) derived from 䡲 Humoral hypercalcemia of malignancy:
ΠPTHrp, usually lung, esophagus, head
circulating progenitor cells, osteocytes that
are “old” osteoblasts embedded in bone and and neck, renal cell, ovary bladder
transmit pressure signals 䡲 Local osteolytic hypercalcemia, includ-
● Osteoblasts regulate osteoclast activity via ing:
osteoprotegerin/receptor activator nuclear ΠBreast and multiple myeloma
receptor ␬ ligand (OPG/RANK-L) system Œ Tumors produce factors such as trans-
䡲 RANK is on osteoclasts and can be forming growth factor ␤ or interleu-
activated by RANK-ligand (RANK-L) kin 1, cytokines such as lympho-
on osteoblasts toxin, or hormones such as calcitriol
䡲 OPG is secreted by osteoblasts and can 䡲 Hematologic malignancy (lymphoma)
bind to RANK-L on osteoblasts, block- with ectopic production of 1,25-dihy-
ing RANK-L binding to RANK oste- droxyvitamin D
oclasts; this serves as a decoy receptor ● All other causes (10%) including drugs
䡲 If increased OPG, less binding of (thiazides, lithium, vitamin D), immobiliza-
RANK-L to RANK and decreased oste- tion, pheochromocytoma, thyrotoxicosis,
oclast activity; if decreased OPG, in- milk-alkali
creased binding of RANK-L to RANK
and increased osteoclast activity
䡲 OPG/RANK system is regulated by By target organ:
nearly all hormones, growth factors, cy- ● Parathyroid gland: Excess release of PTH
tokines known to affect bone turnover in hyperparathyroidism, lithium, familial
hypercalcemia hypocalciuria
HYPERCALCEMIA ● Intestine: Vitamin D toxicosis, sarcoidosis,
granulomatous disorders, milk-alkali syn-
History drome, some tumors
● Malignancy ● Bone: Hyperparathyroidism, thyrotoxico-
● Constitutional symptoms sis, immobilization
● Medication use (thiazides, lithium)
● Family history Diagnostic Tests
Signs and Symptoms ● Ca, PTH, 25(OH)D and 1,25(OH)2D levels,
● Nausea PTHrp
216 SHARON M. MOE

Treatment ● Pancreatitis
Acute ● Pseudohypoparathyroidism
● Hypomagnesemia
● Volume repletion with saline, loop diuret-
● Increased P (binds more Ca): rhabdomyoly-
ics, careful monitoring ins/outs, bisphospho-
sis, tumor lysis syndrome
nate and/or calcitonin if severe
● Hungry bone syndrome
Granulomatous disorders
Diagnostic Tests
● Corticosteroids
● Ca, albumin, Mg, P, PTH, 25(OH)D, and
Chronic/preventive 1,25(OH)2D levels
● Bisphosphonates for bone etiology, calcimi- Treatment
metics for hyperparathyroidism and parathy-
roid malignancy Treat symptoms, not numbers:
Severe
HYPOCALCEMIA ● Parenteral Ca salts for severe or life-threaten-
ing symptoms (2 ampules Ca gluconate 90
History mg Ca/10 mL) or intravenous Ca infusion: 60
● Previous thyroid, parathyroid, or neck sur- mL in 500 mL D5W (1 mg/mL), infuse at 0.5
gery to 2.0 mg/kg/h to control symptoms
● Chronic kidney disease
● Diarrhea Chronic or not severe
● Steatorrhea ● Oral Ca supplements and vitamin D as soon
● Previous bowel surgery as feasible
● Lack of sunlight
● Low dietary Ca and vitamin D Mg depleted
● Replace with Mg salts before giving calcium
Signs and Symptoms
● Neck scar HYPOPHOSPHATEMIA
● Positive Chvostek’s, positive Trousseau’s
signs Low serum P does not necessarily indicate
● Carpal-pedal spasm total body depletion as only 1% of body P is in
● Perioral numbness blood.
● Tetany
● Dyspnea History
● Stridor ● Observed in 10% of hospitalized alcoholics
● Wheezing ● Gastrointestinal disorders, diarrhea, recent
● Seizures severe illness, weight change
● Bone pain ● Diabetic ketoacidosis
● Muscle weakness ● Critical illness/ventilated: Observed in 3%
● Cataracts of all hospitalized patients, up to 70% of
● Rachitic deformities intensive-care-unit patients
● On total parenteral nutrition
Differential Diagnosis ● New medications, renal transplant
● Low albumin (correct Ca level for albumin
to make sure true hypocalcemia) Symptoms
● Hypoparathyroidism: postsurgical, postra- ● Muscle weakness
diation, congenital, autoimmune ● Hypoventilation
● Vitamin D deficiency: renal failure, poor ● Confusion
nutrition, malabsorption, short bowel, cir- ● Seizures
rhosis ● Osteomalacia
CORE CURRICULUM IN NEPHROLOGY 217

Differential Diagnosis Differential Diagnosis

Usually occurs due to combination of 1 of these ● Hyperphosphatemia occurs almost exclu-
3 causes: sively with impaired glomerular filtration
● Decreased intestinal absorption: Antacid rate
abuse, malabsorption, chronic diarrhea, vi- ● Other rare causes:
tamin-D deficiency, starvation, anorexia, 䡲 Increased renal reabsorption: hypopara-
alcoholism thyroidism, acromegaly, thyrotoxicosis
● Increased urinary losses: Primary hyperpara- 䡲 Massive release from intracellular stores in
thyroidism, post–renal transplant, extracel- tumor lysis syndrome, rhabdomyolysis
lular fluid volume expansion, glucosuria 䡲 Overdose of vitamin-D derivatives, phos-
(after treating diabetic ketoacidosis), post– phate-containing enemas
obstructive or resolving acute tubular necro-
sis diuresis, acetazolamide, Fanconi’s syn- Diagnostic Tests
drome, X-linked and vitamin-D–dependent ● Serum P and creatinine/glomerular filtra-
rickets, oncogenic osteomalacia tion rate
● Extracellular to intracellular shift: Respira-
tory alkalosis, alcohol withdrawal, severe Treatment
burns, total parenteral nutrition, recovery Acute symptomatic hyperphosphatemia
from malnutrition when inadequate P is ● Intravenous volume repletion with normal
provided (post–feeding syndrome), leuke- saline will enhance renal excretion, add
mic blast crisis 10 U insulin and 1 ampule D50 to enhance
Diagnostic Tests cellular uptake; best removal is obtained
with dialysis but this is limited due to
● Based on history and trend in values, and intracellular location of P
blood pH (to distinguish acute shift) and
urine P (⬍100 mg/d ⫽ gastrointestinal loss Chronic
or shift) ● Dietary restriction and phosphate binders
Treatment
● Phosphate comes as Na-phosphate or K- HYPERMAGNESEMIA
phosphate; choice dictated by other ill-
nesses such as heart or renal failure History
● Only treat symptomatic severe hypophos- ● Medication use
phatemia with intravenous agents ● Laxative abuse
● Otherwise choose oral agent; oral repletion ● Kidney disease
best done with milk
Signs and Symptoms
HYPERPHOSPHATEMIA ● Lethargy
● Nausea
History ● Confusion
● Renal failure ● Hypoventilation
● Tumor lysis syndrome ● Hypotension
● Rhabdomyolysis ● Arrhythmias
● Muscle weakness
Symptoms ● Decreased deep-tendon reflexes
● Asymptomatic unless hypocalcemia occurs
due to precipitation of insoluble Ca-P com- Differential Diagnosis
plexes and decreased calcitriol synthesis (Occurs almost exclusively with chronic kidney
● Chronic hyperphosphatemia in renal failure disease)
is associated with vascular calcification and ● Increased intake: Antacids, laxatives, enemas,
increased mortality or treatment of preeclampsia with Mg salts
218 SHARON M. MOE

● Decreased renal function Redistribution from extracellular to

● Cellular shifts: Pheochromocytoma, acidosis intracellular fluids
● Insulin administration post-therapy of dia-
Diagnostic Tests
betic ketoacidosis, hungry-bone syndrome
● Mg, creatinine postparathyroidectomy, catecholamine ex-
cess states such as ethanol-withdrawal syn-
Treatment drome, acute pancreatitis, excessive
● Ca can be given if life-threatening arrhyth- lactation
mias, otherwise dialysis
Reduced absorption
● Specific gastrointestinal Mg malabsorption,
HYPOMAGNESEMIA
generalized malabsorption syndrome, post–
extensive bowel resections, diffuse bowel
History disease or injury, chronic diarrhea, laxative
● Alcohol use abuse
● Diarrhea/malabsorption
● Medications (cisplatin, aminoglycosides, Diagnostic Tests
amphotericin, loop diuretics, digoxin) ● Determining Mg deficiency
䡲 Only parameter to consistently predict
Signs and Symptoms
Mg depletion is retention of ⬎75% of
● Tremor of extremities and tongue, myo- Mg after a Mg infusion
clonic jerks, Chvostek sign, Trousseau sign, 䡲 Low urine fractional excretion of Mg
tetany, general muscular weakness (particu- indicative of deficiency
larly respiratory muscles), coma, vertigo, ● Very low serum value (⬍1 mg/dL [0.41
nystagmus, movement disorders mmol/L]) always indicates significant defi-
● Electrocardiogram: Increased susceptibility cits that require therapy
to digoxin-related arrhythmias; ventricular ● Other findings: Hypocalcemia, hypokalemia
arrhythmias: premature ventricular contrac-
tions, ventricular tachycardia, Torsade de Treatment
Pointes, ventricular fibrillation Symptomatic
Differential Diagnosis ● Intravenous Mg sulfate
Reduced intake Asymptomatic
● Starvation, alcoholism, prolonged postop- ● Oral repletion with Mg supplement (Mg
erative state oxide, Mg lactate)