Download Ca/PO4

Renal Pathophysiology: Disorders of Calcium Metabolism (Mohanty)
CALCIUM HOMEOSTASIS:

Calcium Basics:
Most abundant divalent cation in the body (2% of total body weight)
Plays a major role in severe physiologic functions:
o Bone formation
o Nerve conduction
o Muscle contraction
o Blood coagulation
o Cell division and growth
o Hormone secretion

Distribution of Total Body Ca:
99% of body Ca in the bones and teeth
1% in the intracellular and extracellular spaces

Calcium Balance:
Normal Dietary Intake: 1000mg/day
Amount Absorbed in the Intestines: net 200mg/day absorption
o 400mg absorbed
o 200 mg secreted in digestive juices
Amount Excreted in the Urine: 200mg/day
Amount Excreted in the Feces: 800mg/day

Extracellular Calcium:
Three Forms:
o Ionized (50%): physiologically significant form (can be filtered)

Alterations in free Ca lead to SYMPTOMS of hypo- or hypercalcemia*
o Complexed with Anions (10%): citrate, phosphate, bicarbonate, lactate (can be filtered)
o Protein Bound (40%): mostly to albumin (not filtered)

Factors Affecting Ionized Calcium Levels:
pH:
o Acidosis: H+ ion displaces Ca from plasma protein increased IONIZED Ca (unchanged total Ca)
o Alkalosis: H+ is displaced from plasma protein by Ca decreased IONIZED Ca (unchanged total Ca)
o Consequences of Above:

Patients with hypocalcemia (low TOTAL Ca) and ALKALOSIS are more susceptible to have
symptoms of hypocalcemia than patients with ACIDOSIS
 Why? Patients with alkalosis have lower ionized (free) Ca levels
Hypoalbuminemia:
o 40% of the plasma Ca is bound to albumin
o Therefore, decrease in albumin leads to decrease in albumin bound Ca
o Decreases TOTAL serum Ca concentration WITHOUT affecting ionized Ca
o Labs check TOTAL serum Ca concentration (not just ionized)

Therefore, if a patient has low serum Ca, need to check and see if the albumin is low

If the albumin is low, need to check ionized Ca level before treating for hypocalcemia
REGULATION OF CALCIUM BALANCE:

Basics:
Ca levels maintained within narrow limits by:
o Variations in INTESTINAL Ca absorption and excretion
o Movement of Ca into and out of BONES
o Variations in RENA Ca absorption and excretion
Ca handling by kidney, intestine and bones controlled by:
o Parathyroid Hormone (PTH)*
o Calcitriol
o Calcitonin

Parathyroid Hormone (PTH):
Secretion:
o Secreted by: chief cells of the parathyroid glands
o Stimulus for Secretion: hypocalcemia
o Inhibitors of Secretion: hypercalcemia, calcitriol, hypomagnesia
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-
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Note: always check for hypomagnesia in patients who are hypocalcemic (will not be able to
maintain adequate Ca levels until Mg is restored and PTH is no longer suppressed)*
Action:
o
o
Bone: stimulates bone resorption by osteoclasts (release Ca and PO4 from the bone)
Kidney:

Increases Ca reabsorption

Increases PO4 excretion* (dominant action on PO4)

Promotes renal conversion of vitamin D to active metabolite, calcitriol
o Intestine:

Calcitriol increases Ca and PO4 reabsorption
Net Effect:
o Increased serum Ca
o Decreased serum PO4 (major effect is excretion by kidneys)
Calcitriol or 1,25(OH)2 Vitamin D3:
Source: absorbed from food or synthesized in the skin after exposure to UV light
Production:
o Liver converts it 25-hydroxy vitamin D3 (calcifediol)
o Kidney converts calcifediol to 1,25-dihydroxy vitamin D3 (calcitriol), which is the active metabolite
Stimuli for Production:
o PTH
o Hypophosphatemia
Action:
o Bone: increases bone resportion (release Ca and PO4 from bone)
o Kidney: decreases Ca and PO4 excretion by kidneys (increases reabsorption)
o Intestine: increases Ca and PO4 absorption* (most important)
Net Effect:
o Increased serum Ca and PO4
Calcitriol Action in Tissues:
o Binds vitamin D receptors (VDR) present in many cells (intestinal epithelium, parathyroid cells, kidney
cells, osteoblasts)
o Binding of VDR leads to promotion OR inhibition of transcription of mRNA for proteins regulated by
vitamin D (ie. calcium binding proteins)
Calcitonin:
Secretion:
o Secreted by: parafollicular cells of the thyroid gland
o Stimulus for Secretion: increased plasma Ca concentration
Action:
o Bone: blocks Ca resorption from bone and stimulates Ca deposition into bone (predominant action)*
o Kidney: relatively minor effects

Decreases urinary Ca excretion (increases reabsorption)

Increases PO4 excretion
Net Effect:
o Decrease plasma Ca concentration
o Little to no effect on plasma phosphorous concentration
Summary Table of Hormone Effects on Ca and PO4:
[Ca]
[PO4]
PTH
↑
↓
Calcitriol
↑
↑
Calcitonin
↓
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SENSING PLASMA CALCIUM CONCENTRATION:

Calcium Sensing Receptors:
Structure: G protein coupled polypeptide receptor that binds extracellular Ca
Location: expressed in the plasma membrane of cells involved in regulating Ca homeostasis
o Chief cells of parathyroid gland (secrete PTH)
o Parafollicular cells of thyroid (secrete calcitonin)
o Renal tubular cells (PT cells produce calcitriol; TALH and distal tubules reabsorb Ca)
-

Activity:
o Increased Plasma [Ca]: leads to increase in binding of calcium to CaSR

Binding activates intracellular signals, and ultimately results in a decrease in plasma [Ca]
 Inhibit PTH production
 Inhibit calcitriol production
 Stimulate secretion of calcitonin
 Inhibition of Ca reabsorption by TALH and distal tubule
o Decreased Plasma [Ca]: the opposite will occur
CaSR Regulation of Calcium Excretion by Kidneys:
o Basics: CaSR in the TALH and distal tubule regulate Ca absorption by these segments
o Increased Plasma [Ca]: activates CaSR and inhibits reabsorption
o Decreased Plasma [Ca]: increases Ca reabsorption
Secondary Hyperparathyroidism in CKD:
High Serum Phosphorous: patients with CKD have high serum PO4 since the kidney is not filtering it
o Causes a decrease in plasma ionized [Ca] (increased binding to PO4)  INCREASED PTH
o Can also directly stimulate PTH secretion  INCREASED PTH
Low Calcitriol: kidney not functional and therefore cannot convert vitamin D to active form
o Calcitriol not present to suppress PTH INCREASED PTH
o Low serum Ca (not absorbing as much in intestine)  INCREASED PTH
Skeletal Resistance to PTH Action INCREASED PTH
Decreased Number of CaSR:
o PTH secretion cannot be turned off (cannot detect when Ca is high)  INCREASED PTH
RENAL HANDLING OF CALCIUM:

Basics:
Ionized and complexed Ca can be filtered at the glomerulus (Ca bound to albumin is not filtered)
Roughly 1-3% of the filtered Ca is not reabsorbed and excreted in the urine

Proximal Tubule: reabsorbs 60% of filtered Ca
Paracellular Route (90%): the more Na reabsorbed, the more Ca reabsorbed (and vice versa)*
o Na is reabsorbed and H2O follows down osmotic gradient
o Reabsorption of water leads to increase in [Ca] in tubular lumen promotes Ca reabsorption
Transcellular Route (10%): not really dependent on Na reabsorption*
o Ca reabsorbed across luminal membrane via Ca permeable channels
o Extruded across basolateral membrane by:

Ca-ATPase

3Na/Ca exchanger

Thick Ascending Limb of Henle: reabsorbs 20-30% if filtered Ca
Paracellular Route (50%): the more Na reabsorbed by NKCC2, the more Ca reabsorbed (and vice versa)*
o Na is reabsorbed across the apical membrane via NKCC2

Reabsorbed Na and Cl exit basolateral membrane

K leaks back into tubular lumen via ROMK channels
o Secretion of K+ back into tubular lumen gives the lumen and POSITIVE charge
o Luminal + charge drives reabsorption of Ca

Facilitated by cation specific paracellular channels (formed by tight junction proteins claudin
16 and claudin 19)

Mutations in these proteins can lead to impaired Ca (and other cations) reabsorption
increased urinary excretion
o Regulation of Ca reabsorption occurs via the CaSR (basolateral membrane)

When serum Ca is high, binds to this receptor and forms arachadonic acid inhibits ROMK

Result is lack of generation of luminal + charge and decreased paracellular Ca reabsorption
and increased urinary excretion of Ca

Opposite occurs when serum Ca is low
Transcellular Route (50%): similar to proximal tubules

Distal Convoluted Tubule and Connecting Tubule: reabsorbs 10% of the filtered Ca
Transcellular Route (100%): reabsorption of Ca INDEPENDENT of Na reabsorption*
o Ca reabsorbed across apical membrane via TRPV5 channel (highly Ca selective)

Regulated by PTH and calcitriol (both increase TRPV5 activity increase Ca reabsorption)
o Ca crosses basolateral membrane via a Ca-ATPase (PMCA1b) and a 3Na/Ca exchanger (NCX1)
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
Sodium and Calcium Excretion by the Kidney:
Proximal Tubule and Loop of Henle:
o Basics: changes in Na reabsorption result in parallel changes in Ca reabsorption*

Na reabsorption inhibited inhibition of Ca reabsorption excretion of Ca and Na
o Use: treatments for patients with hypercalcemia
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Saline (high salt) inhibits Na (and therefore Ca) reabsorption in the proximal tubule

Loop diuretics inhibits Na (and therefore Ca) reabsorption in the TALH
Distal Tubules: reabsorption of Na and Ca are INDEPENDENT of eachother
o Thiazide Diuretics: used to decrease Ca in the urine (ie. for patients with Ca stones)

Inhibit Na reabsorption increase urinary Na excretion

Stimulated Ca reabsorption decrease urinary Ca excretion
Regulation of Urinary Calcium Excretion:
PTH: ↑ Ca reabsorption in TALH and DT/CNT* (most powerful)
Calcitriol: ↑ Ca reabsorption in the DT/CNT
Calcitonin: ↑ Ca reabsorption in the TALH and DT/CNT
Increased ECF Volume: ↓Ca reabsorption (due to decreased Na reabsorption in the proximal tubule)
Hypercalcemia: ↓Ca reabsorption (binds to CaSR; independent of effects of hormones)
HYPERCALCEMIA:

Definition: elevated calcium levels in the blood (normal typically 8.4-10.5mg/dl)

Causes: more than 90% of cases are cause by primary hyperparathyroidism and malignancy*
Increased calcium mobilization from bone
Increased calcium absorption from GI tract
Decreased urinary calcium excretion

Increased Calcium Mobilization from Bone:
Hyperparathyroidism:
o Parathyroid adenoma
o Hyperplasia of parathyroid
o Parathyroid carcinoma (rarely)
o Part of multiple endocrine neoplasia (MEN; rarely)

Type I (with pituitary and pancreatic tumors)
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Type II (with medullary carcinoma of thyroid and pheochromocytoma)
Malignancy:
o Local Osteolytic Hypercalcemia: occurs with extensive bone involvement

Tumor cells produce products (ie. cytokines) that act locally to stimulate osteoclastic bone
resorption increased Ca
o Humoral Hypercalcemia of Malignancy: no direct bone invasion

Basics: tumor cells produce and release agents into circulation that cause bone resorption

PTH Related Protein (PTHrP): structurally related to PTH (amino acid terminal region)
 Binds and acts on PTH receptors
 However, cannot be detected by PTH immunoassays

Other Mediators:
 TGFα
 IL-1α
 IL-1β
 CSF

Common Causes:
 Squamous cell carcinoma of the lung
 Squamous cell carcinoma of the head and neck
 Squamous cell carcinoma of the esophagus
 Renal cell carcinoma
 Bladder carcinoma
 Ovarian carcinoma
Immobilization
Vitamin D Intoxication

Increased Reabsorption of Calcium from the GI Tract:
Granulomatous Disease:
o Examples: sarcoidosis, TB, leprosy, berylliosis, histoplasmosis, disseminated candidiasis etc.
o Mechanism: granulomas convert 25-hydroxy vitamin D to calcitriol (active form)
Vitamin D Toxicity:
o Patients with renal failure or hypoparathyroidism being treated with vitamin D supplements
Milk Alkali Syndrome:
o Ingestion of large amounts of milk
o CaCO3 intake (tums)
Decreased Urinary Calcium Excretion:
Thiazide Diuretics: stimulate Ca reabsorption by DT
Familial Hypocalciuric Hypercalcemia:
o Inheritance: autosomal dominant (rare)
o Mutation: INACTIVATING mutations in CaSR
o Results: PTH secretion not suppressed by elevated Ca

Increased PTH secretion leads to HYPERCALCEMIA

Increased PTH and defective CaSR leads to increased Ca reabsorption and HYPOCALCIURIA
o Clinical Features:

Asymptomatic hypercalcemia from childhood
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Family history of hypercalcemia
Clinical Manifestations of Hypercalcemia: vary with degree of hypercalcemia and rapidity of onset*
Renal Manifestations:
o Polyuria: inability to concentrate urine

Decreased Na transport in TALH diminished osmotic gradient in medulla

Inhibition of AC and generation of cAMP decreased permeability of collecting duct to
water in response to ADH
o Nephrocalcinosis
o Nephrolithiasis
o Renal Failure:

Vasoconstriction of afferent arterioles

Volume depletion because of increased urinary Na excretion and polyuria

Nephrolithiasis causing obstruction
o Increased urinary Ca++ excretion
o Increased urinary Na+ excretion
Other Manifestations:
o Anorexia, N/V, constipation
o Weakness, fatigue, confusion, stupor, coma
o Dehydration
o Ectopic soft tissue calcification
Diagnosis:
History and Physical:
o Clinical evidence of ANY disease that causes hypercalcemia (including signs of malignancy)
o Intake of medications that cause hypercalcemia
o Clinical features of hypercalcemia (N/V, confusion, lethargy, renal stones)
Laboratory Tests:
o PTH Levels: newer assays detect only intact PTH (intact PTH levels/whole PTH levels)

PTH levels should be SUPPRESSED in patients with hypercalcemia

PTH levels inappropriately NORMAL in patients with hypercalcemia due to increased
inappropriate PTH secretion (ie. hyperparathyroidism)

PTH levels are SUPPRESSED in patients with hypercalcemia due to malignancy (not due to
PTH itself; recall PTHrP is NOT measure by this assay)
o Calcitriol Levels:

Elevated in vitamin D intoxication and granulomatous disease
o PTHrP Levels:

Elevated in humoral hypercalcemia of malignancy
EKG: shortened QT interval
Clinical Management:
Acute Management:
o ECF Volume Restoration: restoration of GFR and increased Ca excretion
o Saline Diuresis: promotes urinary Ca excretion after ECF volume has been restored (LOOP DIURETICS)
o Bisphosphonates: inhibit bone resorption
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o
o
o
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Calcitonin: inhibit bone resorption
Pliamycin: inhibits bone resorption (not really used anymore)
Glucocorticoids:

Many possible functions:
 Inhibits cytokine release
 Direct cytolytic effect on some tumor cells
 Inhibit intestinal Ca absorption
 Increases urinary Ca excretion

Effective use in:
 Hypercalcemia due to myeloma or other hematological malignancies
 Sarcoidosis
 Vitamin D intoxication
o Dialysis: in patients with renal failure or CHF (can’t give a ton of fluids)
Chronic Management:
o Treat underlying cause*
HYPOCALCEMIA:

Definition: low calcium levels in the blood

Important Point About Hypoalbuminemia:
Hypoalbuminemia: if hypocalcemia is accompanied by hypoalbuminemia, total serum calcium may be decreased
by IONIZED calcium levels may be normal (need to specifically measure ionized Ca)
o If Ionized Ca Normal: no disorder of calcium metabolism, patient will remain asymptomatic
o If Ionized Ca Can’t be Measured: total calcium can be corrected to determine if true hypocalcemia is
present

Basics: add 0.8mg/dl for every gram decrease in serum albumin below 4g/dl

Example: total serum Ca is 6mg/dl and albumin is 1 mg/dl
 3 x 0.8mg/dl= 2.4mg/dl
 Corrected calcium= 6 + 2.4= 8.4mg/dl (not true hypocalcemia)

Causes of Hypocalcemia:
Hypoparathyroidism: most commonly due to surgical removal of parathyroid gland
Vitamin D Deficiency:
o Decreased ingestion
o Decreased absorption (partial gastrectomy, intestinal bypass)
o Deficiency in 25-hydroxy vitamin D3 (liver disease, anticonvulsants)
o Deficiency in 1,25-dihydroxy vitamin D3 (advanced renal failure, hypoparathyroidism decreased PTH)
Bone Resistance to PTH Effects:
o Pseudohypoparathyroidism
Hypomagnesemia:
o Inhibits PTH release
Precipitation of Ionized Calcium: complexed to increased anions in the blood*
o PO4 retention (advanced renal failure)
o Severe rhabdomyolysis
o Tumor lysis syndrome
o Multiple citrated blood transfusions (ionized Ca complexed to citrate in blood)
Miscellaneous Conditions:
o Acute Pancreatitis: deposition of Ca salts in areas of lipolysis
o Drugs: that decrease bone resorption
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Calcitonin

Mithramycin
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Colchicine
o Autosomal Dominant Hypocalcemia: rare*

Mutation: ACTIVATING mutations in CaSR

Result: PTH is suppressed at lower serum Ca levels
 Decreased PTH HYPOCALCEMIA
 Decreased PTH + defective CaSR regulation ↓Ca reabsorption (HYPERCALCIURIA)

Clinical Features:
 Asymptomatic hypocalcemia from childhood
 Family history of hypocalcemia


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Clinical Features: vary with degree of hypocalcemia and rapidity of onset*
Important Point About Alkalosis:
o Recall that alkalosis AUGMENTS binding of Ca to albumin decreased ionized Ca
o Therefore, alkalosis with hypocalcemia results in INCREASED SEVERITY of symptoms
Characteristic Features:
o Increased neuromuscular irritability parasthesias and tetany

Trousseau’s Sign: carpal spasm when BP cuff is inflated above systolic pressure for 3 minutes

Chvostek’s Sign: twitching of facial muscles when facial nerve is tapped anterior to ear
Other Features:
o Lethargy
o Confusion
o Laryngospasm
o Seizures
o Heart failure
o Proximal musle weakness (in cases of vitamin D deficiency)
Diagnosis:
History and Physical:
o History of neck surgery (parathyroidectomy)
o Drugs that cause hypocalcemia or hypomagnesemia
o Family history of hypocalcemia
o Conditions that cause vitamin D deficiency
o Findings of pseudohypoparathyroidism (short stature,short metacarpals)
o History of renal failure
Laboratory Tests:
o Free ionized Ca
o Phosphorous
o Magnesium
o Creatinine
o Intact PTH
EKG: prolonged QT interval
Treatment:
Acute Management: treat if symptomatic
o Calcium supplements
o Treat hypomagnesemia if present
Long-Term Management:
o Calcium supplements
o Vitamin D supplements