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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
TAHL mechanism of calcium reabsorption
A paracellular mechanism accounts for the transport of calcium in this segment
26
TAHL calcium reabsorption USMLE implications
* Mutations of ROMK/NKCC2/Claudin/bartin * Loop diuretics and mechanism of action in treating hypercalcemia
27
Genetic disorders of TAHL
are associated with hypercalciuria Mutations of ROMK or the NKCC2 lead to **Bartter's Syndrome**
28
Bartter's syndrome key features
manifestations similar to giving furosemide * Salt-wasting * hypokalemic alkalosis * hypercalciuria
29
Bartter's Syndrome manifestations are similar to giving?
**Furosemide** * Salt-wasting * hypokalemic alkalosis * hypercalciuria
30
CD **Main** mechanism of calcium reabsorption
A transcellular mechanism accounts for the transport of calcium in this segment
31
TAHL **MAIN** mechanism of calcium reabsorption
A paracellular mechanism accounts for the transport of calcium in this segment
32
PT **MAIN** mechanism of calcium reabsorption
80% passive diffusion (paracellular) 10-15% active transport (intracellular)
33
CD mechanisms of calcium reabsorption
* 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
34
Disorders of distal calcium transport
* (Mutations of NCC) Gittelman syndrome * thiazide diuretics (act on NCC) * Hypocalciuria and hypercalcemia (low potassium, metabolic alkalosis
35
Gittelman syndrome genetics
Mutations of NCC
36
NCC is acted on by what kind of diuretics?
Thiazide diuretics
37
Hypocalciuria and hypercalcemia cause
* low potassium * metabolic alkalosis
38
Hormones that regulate calcium homeostasis
* Parathyroid hormone * Calcitriol
39
PTH AKA
Parathyroid hormone
40
Where is parathyroid hormone produced?
Parathyroid glands
41
Where is calcitriol produced?
Kidneys
42
On what tissues do the hormones of calcium homeostasis act on?
* Bone * Intestine * Kidneys
43
How are the hormonal regulatory systems of calcuim homeostasis feedback loops coordinated?
Calcium-sensing receptor is the key sensor coordinating the various feedback loops in the kidneys and parathyroid glands
44
Explain the parathyroid hormone feedback loop for calcium homeostasis
45
States that influence the parathyroid hormone calcium homeostatic system 3 listed
* Hypocalcemia * Hyperphosphatemia * Decreased calcitriol
46
Receptors for the parathyroid hormone calcium homeostatic system 2 listed
* Calcium-sensing receptor * Vitamin-D receptor
47
Where is parathyroid hormone secreted from and in response to what stimuli?
From the parathyroid glands in response to: * hypocalcemia * Hyperphosphatemia * Decreased calcitriol
48
The secretion of PTH causes what? 4 listed
* Stimulates bone resorption * Augements renal calcium * enhances renal calcitriol production * GI absorption of calcium and phosphorus
49
General mechanisms of hypocalcemia 4 listed
* Lack of PTH * Lack of Vitamin D * Increased calcium complexation * Disorders of the calcium-sensing receptor
50
General mechanisms of hypercalcemia 6 listed
* 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
Diuretics that decrease calcium excretion
Thiazides
52
How can Thiazides influence calcium levels
can cause hypercalcemia from decreased renal excretion of calcium
53
Factors that **increase** calcium reabsorption 6 listed
* Hyperparathyroidism * Calcitriol * Hypocalcemia * Volume contraction * Metabolic alkalosis * thiazide diuretics
54
Factors that **decrease** calcium reabsorption 6 listed
* Hypoparathyroidism * low calcitriol levels * hypercalcemia * extracellular fluid expansion * metabolic acidosis * loop diuretics
55
Manifestations of hypocalcemia 6 listed
* Mild is asymptomatic * large changes lead to symptoms due to increased neuromuscular activity * Perioral paresthesias * carpopedal spasms * Trousseau sign * Chvostek sign
56
Manifestations of hypercalcemia 8 listed
* GI symptoms (nausea, vomiting, constipation) NVC * Difficulty concentrating * lethargy * muscle weakness * hypertension shortening QT interval * urinary concentrating defect (Diabetes insipidus) * Volume depletion
57
Trousseau sign
Trousseau's sign is carpopedal spasm caused by inflating the blood-pressure cuff to a level above systolic pressure for 3 minutes
58
Chvostek's sign
Chvostek's sign is described as the twitching of facial muscles in response to tapping over the area of the facial nerve
59
Signs of hypocalcemia
* Trousseau sign * Chvosteks sign
60
Primary hyperparathyroidism 5 listed
* 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
Secondary hyperparathyroidism
* 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
Secondary hyperparathyroidism is usually due to?
Chronic kidney disease or Vitamin D deficiency
63
What is tertiary hyperparathyroidism?
* 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
Tertiary hyperparathyroidism clues to presence
* Does not respond to medical therapy (vitamin D analogs/calcimimetics) * hypercalcemia
65
Treatment of tertiary hyperparathyroidism
Therapy is surgical (parathyroidectomy)
66
Humoral hypercalcemia prevalence
observed in 10-20% of patients with cancer
67
Humoral hypercalcemia etiology
Due to the secretion of parathyroid hormone-related peptide (PTHrP) by the tumor cells
68
PTHrP AKA
Parathyroid hormone-related peptide
69
PTHrP physiology
PTHrP has the same physiologic action as PTH and thus appropriately shut down the production of PTH * hypercalcemia * hypercalciuria
70
Humoral hypercalcemia lab profile
* Elevated calcium * elevated PTHrP * decreased PTH * decreased 1, 25 dihydroxyvitamin D3 levels (calcitriol synthesis is PTH dependent)
71
1, 25 dihydroxyvitamin D3 AKA
Calcitriol
72
Calcitriol AKA
1, 25 dihydroxyvitamin D3
73
Thiazides and calcium
Hypercalcemia is a side effect of thiazide use * Usually in older women * 25% will also have evidence of primary hyperparathyroidism ("two hit")
74
Proposed mechanisms of Thiazide and calcium 2 listed
* 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
Effects of thiazides on urinary calcium
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
Some examples of thiazides
* Hydrochlorthiazide * Clorthalidone
77
Hydrochlorothiazide drug class
Thiazide diuretic
78
Chlorthalidone drug class
thiazide diuretic
79
What type of receptor is the calcium-sensing receptor?
G protein-coupled membrane receptor
80
What activates the calcium-sensing receptor?
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
Where are calcium-sensing receptors located?
They are extensively present in the **parathyroid glands** and the **kidney**
82
83
Diseases caused by **Inactivating** mutations of the CaSR 2 listed
* Familiar hypocalciuric hypercalcemia * Neonatal severe hyperparathyroidism
84
CaSR AKA
Calcium-sensing receptor
85
Familiar hypocalciuric hypercalcemia etiology
heterozygous Autosomal dominant inactivating mutations of the CaSR
86
Familiar hypocalciuric hypercalcemia features 5 listed
* 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
Neonatal severe hyperparathyroidism etiology
* Homozygous autosomal dominant inactivating mutations of CaSR gene
88
Neonatal severe hyperparathyroidism features
* homozygous autosomal dominant inactivating mutation of CaSR * Severe hypercalcemia * Severe bone demineralization * Hyperparathyroidism * Requires parathyroidectomy
89
Neonatal severe hyperparathyroidism treatment
Requires parathyroidectomy
90
Most common inactivating mutation of the CaSR
Familial hypocalciuric hypercalcemia
91
Familial hypocalciuric hypercalcemia advanced genetics
* FHH type 2 via mutations of the GNA11 gene (10%) * FHH type 3 via mutations of the AP2S1 gene (15%)
92
FHH AKA
Familial hypocalciuric hypercalcemia
93
FHH type 2 mutation
GNA11 gene (10%)
94
FHH type 3 mutations
APS21 gene (15%)
95
What is the explanation of pathology for diseases caused by inactivating mutations of the CaSR?
The body thinks there is too little calcium around
96
Diseases caused by **activating** mutations of the CaSR
* Hypercalciuric hypocalcemia syndrome type 1
97
HHS1 AKA
Hypercalciuric hypocalcemia syndrome type 1
98
Hypercalciuric hypocalcemia syndrome type 1 AKA
Autosomal dominant hypocalcemia
99
Hypercalciuric hypocalcemia syndrome type 1 etiology
* Autosomal dominant activating mutations of CaSR
100
Hypercalciuric hypocalcemia syndrome type 1 features 6 listed
* Autosomal dominant activating mutations of CaSR * hypocalcemia * relative hypercalciuria * Nephrocalcinosis * Etopic calcifications * Nephrolithiasis
101
Hypercalciuric hypocalcemia syndrome type 1 pathophysiology
* 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

CVPR (93 decks)

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