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CVPR > CVPR Week 8: Renal handling of Ca > Flashcards

CVPR Week 8: Renal handling of Ca Flashcards

1
Q

Objectives

A
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2
Q

What is the total body content of calcium?

A

1000-1200 g

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3
Q

Where does most of the body’s calcium reside?

A
  • 99% resides in bone
  • 0.9% is intracellular
  • 0.1% is extracellular
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4
Q

Describe the chemical anatomy of serum calcium

A
  • 48% is ionized
  • 46% is protein bound
  • 7% is complexed with inorganic compounds
    *
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5
Q

Describe ionized calcium

A

physiologically active in muscle contraction, blood coagulation and intracellular adhesion

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6
Q

Describe protein-bound calcium

A
  • hypoalbuminemia may result in falsely low levels (may correct by adding 0.8 for the reduction of albumin by 1 unit below 4 g/dL)
  • Effect on calcium levels is testable: either do the correction or ask for an ionized calcium level if you are given the option in a MCQ
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7
Q

Describe complexed calcium

A

complexed with inorganic compounds such as citrate or phosphate

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8
Q

Describe calcium flux between body compartments

A

moment-to-moment maintenance of plasma calcium primarily involves calcium flux between bone and plasma

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9
Q

Describe intestinal calcium absorption

A

There are 2 main mechanisms of intestinal calcium absorption:

  • Paracellular (between cells)
  • Through cells
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10
Q

Describe paracellular calcium intestinal absorption

A

(Between cells)

  • Passive
  • Quantitatively significant when intake is high
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11
Q

Describe intestinal absorption of calcium through cells

A
  • Active process
  • influenced by calcitriol
  • Calbindin acts as an intracellular sink to reduce the microvilli [Ca]
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12
Q

Calbindin function

A

Acts as an intracellular sink to reduce microvilli [Ca]

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13
Q

Describe Calcitriol effect on intestinal calcium uptake

A
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14
Q

What chemical forms of serum calcium can be directly manipulated by the kidneys?

A

Only the ionized and complexed calcium may be directly affected by the kidneys

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15
Q

What is the typical filtered load of calcium/day

A

Filtered load of 10g of calcium/day

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16
Q

How much calcium can be found in the urine?

A

normally only 200 mg are found in the urine

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17
Q

How much calcium is absorbed by the urine?

A

typically 98-99% is absorbed by the kidneys

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18
Q

Where is calcium absorbed in the renal system?

A
  • The proximal convoluted tubule does ~60-70%
  • DCT does ~10%
  • thick limb of the ascending loop of Henle does 20%
  • CD does 5%
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19
Q

Prevent kidney stones USMLE implications

A
  • Reduce salt intake to prevent kidney stones
  • Thiazides reduce hypercalciuria and prevent kidney stones and osteoporosis
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20
Q

Osteoporosis and diuretics

A

Thiazides reduce hypercalciuria and prevent kidney stones and osteoporosis

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21
Q

Renal regulation of calcium absorption occurs where?

A

Distally

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22
Q

What treatment for hypercalcemia?

A
  • Saline because salt loading will cause hypercalciuria and promote kidney stones
  • Any factor that increases distal delivery of sodium will in general promote renal excretion of calcium
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23
Q

Proximal tubule mechanism of calcium reabsorption

A

80% passive paracellular

10-15% active transport

  • NHE3 sodium hydrogen antiporter Na(in) H(out)
  • NBC Na HCO3- symporter Na and HCO3-(out)
  • 3Na/2K antiporter Na(in) K(out)
  • TJ Na transporter
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24
Q

TAHL AKA

A

Thick ascending loop of Henle

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25
Q

TAHL mechanism of calcium reabsorption

A

A paracellular mechanism accounts for the transport of calcium in this segment

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26
Q

TAHL calcium reabsorption USMLE implications

A
  • Mutations of ROMK/NKCC2/Claudin/bartin
  • Loop diuretics and mechanism of action in treating hypercalcemia
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27
Q

Genetic disorders of TAHL

A

are associated with hypercalciuria

Mutations of ROMK or the NKCC2 lead to Bartter’s Syndrome

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28
Q

Bartter’s syndrome key features

A

manifestations similar to giving furosemide

  • Salt-wasting
  • hypokalemic alkalosis
  • hypercalciuria
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29
Q

Bartter’s Syndrome manifestations are similar to giving?

A

Furosemide

  • Salt-wasting
  • hypokalemic alkalosis
  • hypercalciuria
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30
Q

CD Main mechanism of calcium reabsorption

A

A transcellular mechanism accounts for the transport of calcium in this segment

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31
Q

TAHL MAIN mechanism of calcium reabsorption

A

A paracellular mechanism accounts for the transport of calcium in this segment

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32
Q

PT MAIN mechanism of calcium reabsorption

A

80% passive diffusion (paracellular)

10-15% active transport (intracellular)

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33
Q

CD mechanisms of calcium reabsorption

A
  • Entry of calcium into the epithelial cells from the apical transient canilloid 5 (TRPV5): controlled by calcitriol and PTH
  • Diffusion of calcium unto the cytoplasm bound to calbidin-D28k
  • Active transport of Ca2+ out of epithelial cells through the sodium-calcium exchanger and the plasma membrane Ca/ATPase
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34
Q

Disorders of distal calcium transport

A
  • (Mutations of NCC) Gittelman syndrome
  • thiazide diuretics (act on NCC)
  • Hypocalciuria and hypercalcemia (low potassium, metabolic alkalosis
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35
Q

Gittelman syndrome genetics

A

Mutations of NCC

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36
Q

NCC is acted on by what kind of diuretics?

A

Thiazide diuretics

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37
Q

Hypocalciuria and hypercalcemia cause

A
  • low potassium
  • metabolic alkalosis
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38
Q

Hormones that regulate calcium homeostasis

A
  • Parathyroid hormone
  • Calcitriol
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39
Q

PTH AKA

A

Parathyroid hormone

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40
Q

Where is parathyroid hormone produced?

A

Parathyroid glands

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41
Q

Where is calcitriol produced?

A

Kidneys

42
Q

On what tissues do the hormones of calcium homeostasis act on?

A
  • Bone
  • Intestine
  • Kidneys
43
Q

How are the hormonal regulatory systems of calcuim homeostasis feedback loops coordinated?

A

Calcium-sensing receptor is the key sensor coordinating the various feedback loops in the kidneys and parathyroid glands

44
Q

Explain the parathyroid hormone feedback loop for calcium homeostasis

A
45
Q

States that influence the parathyroid hormone calcium homeostatic system

3 listed

A
  • Hypocalcemia
  • Hyperphosphatemia
  • Decreased calcitriol
46
Q

Receptors for the parathyroid hormone calcium homeostatic system

2 listed

A
  • Calcium-sensing receptor
  • Vitamin-D receptor
47
Q

Where is parathyroid hormone secreted from and in response to what stimuli?

A

From the parathyroid glands

in response to:

  • hypocalcemia
  • Hyperphosphatemia
  • Decreased calcitriol
48
Q

The secretion of PTH causes what?

4 listed

A
  • Stimulates bone resorption
  • Augements renal calcium
  • enhances renal calcitriol production
  • GI absorption of calcium and phosphorus
49
Q

General mechanisms of hypocalcemia

4 listed

A
  • Lack of PTH
  • Lack of Vitamin D
  • Increased calcium complexation
  • Disorders of the calcium-sensing receptor
50
Q

General mechanisms of hypercalcemia

6 listed

A
  • Excess PTH production or PTH action
  • Excess calcitriol
  • increased bone resorption
  • increased intestinal absorption
  • decreased renal excretion of calcium (thiazides)
  • Disorders of the calcium-sensing receptor
51
Q

Diuretics that decrease calcium excretion

A

Thiazides

52
Q

How can Thiazides influence calcium levels

A

can cause hypercalcemia from decreased renal excretion of calcium

53
Q

Factors that increase calcium reabsorption

6 listed

A
  • Hyperparathyroidism
  • Calcitriol
  • Hypocalcemia
  • Volume contraction
  • Metabolic alkalosis
  • thiazide diuretics
54
Q

Factors that decrease calcium reabsorption

6 listed

A
  • Hypoparathyroidism
  • low calcitriol levels
  • hypercalcemia
  • extracellular fluid expansion
  • metabolic acidosis
  • loop diuretics
55
Q

Manifestations of hypocalcemia

6 listed

A
  • Mild is asymptomatic
  • large changes lead to symptoms due to increased neuromuscular activity
  • Perioral paresthesias
  • carpopedal spasms
  • Trousseau sign
  • Chvostek sign
56
Q

Manifestations of hypercalcemia

8 listed

A
  • GI symptoms (nausea, vomiting, constipation) NVC
  • Difficulty concentrating
  • lethargy
  • muscle weakness
  • hypertension shortening QT interval
  • urinary concentrating defect (Diabetes insipidus)
  • Volume depletion
57
Q

Trousseau sign

A

Trousseau’s sign is carpopedal spasm caused by inflating the blood-pressure cuff to a level above systolic pressure for 3 minutes

58
Q

Chvostek’s sign

A

Chvostek’s sign is described as the twitching of facial muscles in response to tapping over the area of the facial nerve

59
Q

Signs of hypocalcemia

A
  • Trousseau sign
  • Chvosteks sign
60
Q

Primary hyperparathyroidism

5 listed

A
  • primary elevations of PTH
  • normal to high serum calcium
  • Elevated PTH (absolutely or relative to the calcium level
  • Hypophosphatemia (and hyperphosphaturia)
  • Normal renal function (initially - long standing hypercalcemia results in renal damage)
61
Q

Secondary hyperparathyroidism

A
  • Due to chronic kidney disease or vitamin D deficiency
  • Release of PTH is secondary to decreased inhibition at the level of the parathyroids
  • Low-normal serum calclium
  • High serum phosphorus
  • Low or normal Vitamid D
  • Impaired kidney function
62
Q

Secondary hyperparathyroidism is usually due to?

A

Chronic kidney disease

or

Vitamin D deficiency

63
Q

What is tertiary hyperparathyroidism?

A
  • Autonomous function of the parathyroids (primary hyperparapathophysiology) in a patient with long-standing chronic kidney disease/dialysis/transplant
  • Endpoint in the natural history of the secondary hyperparathyroidism
64
Q

Tertiary hyperparathyroidism clues to presence

A
  • Does not respond to medical therapy (vitamin D analogs/calcimimetics)
  • hypercalcemia
65
Q

Treatment of tertiary hyperparathyroidism

A

Therapy is surgical (parathyroidectomy)

66
Q

Humoral hypercalcemia prevalence

A

observed in 10-20% of patients with cancer

67
Q

Humoral hypercalcemia etiology

A

Due to the secretion of parathyroid hormone-related peptide (PTHrP) by the tumor cells

68
Q

PTHrP AKA

A

Parathyroid hormone-related peptide

69
Q

PTHrP physiology

A

PTHrP has the same physiologic action as PTH and thus appropriately shut down the production of PTH

  • hypercalcemia
  • hypercalciuria
70
Q

Humoral hypercalcemia lab profile

A
  • Elevated calcium
  • elevated PTHrP
  • decreased PTH
  • decreased 1, 25 dihydroxyvitamin D3 levels (calcitriol synthesis is PTH dependent)
71
Q

1, 25 dihydroxyvitamin D3 AKA

A

Calcitriol

72
Q

Calcitriol AKA

A

1, 25 dihydroxyvitamin D3

73
Q

Thiazides and calcium

A

Hypercalcemia is a side effect of thiazide use

  • Usually in older women
  • 25% will also have evidence of primary hyperparathyroidism (“two hit”)
74
Q

Proposed mechanisms of Thiazide and calcium

2 listed

A
  • Volume deficit - leads to PT reabsorption of Na+ and decreased distal delivery of salt and water
  • Thiazides inactivate NCC - less Na+ in the cell -> cell hyperpolarizes -> more Ca2+ leaves the cell and enters the circulation through the Ca/ATPase and NCX1
75
Q

Effects of thiazides on urinary calcium

A

Thiazides are effective agents for the treatment of hypertension but will induce a state of hypercalciuria which is desirable when:

  • treating patients with hypertension at risk for osteoporosis
    • Treat hypertension with thiazides and prevent bond calcium loss through hypocalciuria
  • Treating patients at risk (or who already have had) kidney stones
    • Reduced calcium in the urine = reduced kidney stone potential
76
Q

Some examples of thiazides

A
  • Hydrochlorthiazide
  • Clorthalidone
77
Q

Hydrochlorothiazide drug class

A

Thiazide diuretic

78
Q

Chlorthalidone drug class

A

thiazide diuretic

79
Q

What type of receptor is the calcium-sensing receptor?

A

G protein-coupled membrane receptor

80
Q

What activates the calcium-sensing receptor?

A

Type 1 agonists: Activated by Ca2+ and Mg2+ and other poly-cationic molecules (type-1 agonists)

Type 2 agonists: require Ca2+ to activate the receptor (e.g. calcimimetic)

81
Q

Where are calcium-sensing receptors located?

A

They are extensively present in the parathyroid glands and the kidney

82
Q
A
83
Q

Diseases caused by Inactivating mutations of the CaSR

2 listed

A
  • Familiar hypocalciuric hypercalcemia
  • Neonatal severe hyperparathyroidism
84
Q

CaSR AKA

A

Calcium-sensing receptor

85
Q

Familiar hypocalciuric hypercalcemia etiology

A

heterozygous Autosomal dominant inactivating mutations of the CaSR

86
Q

Familiar hypocalciuric hypercalcemia features

5 listed

A
  • Autosomal dominant inactivating mutation of CaSR
  • Hypercalcemia
  • Relative hypocaluria (Ca/CrCl < 0.01)
  • Normal or high plasma PTH (may be confused with 1o hyperparathyroidism)
  • Usually asymptomatic
87
Q

Neonatal severe hyperparathyroidism etiology

A
  • Homozygous autosomal dominant inactivating mutations of CaSR gene
88
Q

Neonatal severe hyperparathyroidism features

A
  • homozygous autosomal dominant inactivating mutation of CaSR
  • Severe hypercalcemia
  • Severe bone demineralization
  • Hyperparathyroidism
  • Requires parathyroidectomy
89
Q

Neonatal severe hyperparathyroidism treatment

A

Requires parathyroidectomy

90
Q

Most common inactivating mutation of the CaSR

A

Familial hypocalciuric hypercalcemia

91
Q

Familial hypocalciuric hypercalcemia advanced genetics

A
  • FHH type 2 via mutations of the GNA11 gene (10%)
  • FHH type 3 via mutations of the AP2S1 gene (15%)
92
Q

FHH AKA

A

Familial hypocalciuric hypercalcemia

93
Q

FHH type 2 mutation

A

GNA11 gene (10%)

94
Q

FHH type 3 mutations

A

APS21 gene (15%)

95
Q

What is the explanation of pathology for diseases caused by inactivating mutations of the CaSR?

A

The body thinks there is too little calcium around

96
Q

Diseases caused by activating mutations of the CaSR

A
  • Hypercalciuric hypocalcemia syndrome type 1
97
Q

HHS1 AKA

A

Hypercalciuric hypocalcemia syndrome type 1

98
Q

Hypercalciuric hypocalcemia syndrome type 1 AKA

A

Autosomal dominant hypocalcemia

99
Q

Hypercalciuric hypocalcemia syndrome type 1 etiology

A
  • Autosomal dominant activating mutations of CaSR
100
Q

Hypercalciuric hypocalcemia syndrome type 1 features

6 listed

A
  • Autosomal dominant activating mutations of CaSR
  • hypocalcemia
  • relative hypercalciuria
  • Nephrocalcinosis
  • Etopic calcifications
  • Nephrolithiasis
101
Q

Hypercalciuric hypocalcemia syndrome type 1 pathophysiology

A
  • In the parathyroids: the body thinks too much calcium is around <-> hypocalcemia
  • In the kidney the defect localizes to TAHL
    • Normally CaSR inhibits sodium transport
    • Activating mutation leads to salt-wasting
    • Salt-wasting promotes calcium loss
    • Hypercalciuria leads to nephrocalcinosis and nephrolithiasis

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