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Pathophysiology - Urinary Tract > Disorders of Calcium Metabolism > Flashcards

Disorders of Calcium Metabolism Flashcards

1
Q

What is the most abundant divalent cation in the body and where is most of it stored?

A

Calcium!

99% of it is stored in the skeleton, the other 1% is present in the intracellular / extracellular spaces

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2
Q

What are the three major players of calcium homeostasis in the body?

A

Three primary organs involved in calcium homeostasis:

Bones, intestines, and kidneys

Intestinal absorption, excretion, and renal excretion maintains constant levels, with the bone constantly being remodelled thru the circulating calcium pool

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3
Q

What are the three forms of extracellular calcium and which is freely filtered?

A

40% is bound to albumin
10% is complexed to anions like citrate, phosphate, bicarbonate, and lactate
50% is ionized, free calcium

Only the ionized, free calcium is filtered at the glomerulus

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4
Q

What effect will hypoalbuminemia have on total serum calcium concentration and clinical decision making?

A

Hypoalbuminemia -> decreased total serum calcium

However, the ionized calcium may stay the same. Clinical decisions should be based on ionized calcium levels in low albumin states -> ionized calcium is what determines the gradient

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5
Q

What will the effect of decreasing pH have on the calcium levels and why? Wat about alkalosis?

A

Decreasing pH in bood will making H+ ions displace Ca+2 from albumin, causing symptoms of hypercalcemia WITHOUT an increase in total calcium concentration

Opposite will occur in alkalosis -> symptoms of hypocalcemia

Both may have same total calcium concentration, but hypo versus hypercalcemia

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6
Q

Who will have a worse clinical picture, a hypocalcemic patient with alkalosis or acidosis?

A

Patient with alkalosis.

Hypocalcemia -> low total serum calcium concentration.

Acidosis will tend to increase the patient’s ionized calcium level, while alkalosis will decrease it.

Ionized calcium level is responsible for the outward symptoms of the patient.

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7
Q

What are the three hormones which regulate calcium homeostasis?

A
  1. Parathyroid hormone
  2. Calcitriol - Vitamin D
  3. Calcitonin
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8
Q

Where is PTH secreted and what are its direct effects on the bone and kidney?

A

Secreted by chief cells of parathyroid glands in response to hypocalcemia

Bone - Increases bone resorption

Kidney - Increases calcium reabsorption with phosphate excretion (dominant effect). Also promotes conversion of vitamin D in kidney by upregulating 1-alpha-hydroxylase

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9
Q

What is the net effect of PTH?

A

Increases calcium reabsorption with decreased phosphate levels (kidney effect is more important than phosphate reabsorption effect from bone)

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10
Q

What are three inhibitors of PTH?

A

Calcitriol
Hypomagnesia - important because hypomagnesia is a cause of hypocalcemia, and can be treated with Mg+2 supplements
Hypercalcemia

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11
Q

What are the effects of calcitriol on the bone, intestines, and kidneys?

A

Bone - increases bone turnover, with increased calcium / phosphate release due to resorption

Intestines - increased absorption of calcium and phosphate

Kidneys - Decreases calcium and phosphate secretion

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12
Q

What is the net effect of calcitriol on calcium and phosphate levels, and what stimulates its release?

A

Increases blood calcium and phosphate levels

Release is stimulated by hypophosphatemia and PTH

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13
Q

What secretes calcitonin and what is its major stimulus? How does this relate to its net effect?

A

Secreted by parafollicular cells of thyroid gland

Release is stimulated by an increase in plasma calcium concentration

Net effect is a decrease in blood calcium levels with no effect on phosphate levels

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14
Q

What effect does calcitonin have on bone, kidney, and intestines? Read this closely!

A

Bone - stops osteoclasts -> decreased bone breakdown, increased bone formation, losing calcium and phosphate

Minor effects:
Kidney - DECREASES urinary calcium excretion (no hormone increases it, only calcium sensing receptors), increases phosphate excretion

Intestine - INCREASES calcium and phosphate reabsorption

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15
Q

How do the parathyroid gland, thyroid gland, and kidneys sense changes in plasma calcium concentration?

A

Calcium sensing receptors - G-protein coupled receptors which bind extracellular calcium.

Each site carries signal differently, but for instance PTH release is decreased by a Gq receptor which increases intracellular calcium, stopping PTH release.

Calcitonin release would be increased.

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16
Q

Where in the nephron is the majority of calcium reabsorbed, and by what primary route? How will a diuretic affect this?

A

Proximal convoluted tubule

Mostly paracellularly via solvent drag, with a small amount transcellularly (absorbed via NCX in exchange for three sodium)

Diuretics decrease calcium reabsorption by failing to concentrate calcium in the proximal tubule, inhibiting its paracellular reabsorption
-> much better if hypercalcemic

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17
Q

How is calcium reabsorbed in the thick ascending loop of Henle and how will diuretics affect this?

A

50% via the transcellular route and 50% paracellular

NKCC pulls in K+, which can be leaked back out thru K+ transporter. This generates the positive intraluminal potential which pushes paracellular calcium reabsorption.

Diuretics block this K+ mechanism and decrease calcium reabsorption

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18
Q

What proteins allow the paracellular reabsorption of calcium in the TALH?

A

Pore is formed by claudin-16 and claudin-19

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19
Q

How the calcium-sensing receptor affect solute transport in the TALH affect calcium transport?

A
  1. Binding of calcium leads to inhibition of apical K+ channel, diminishing the lumen positive charge and hence calcium reabsorption.
  2. Binding of calcium upregulates expression of claudin-14 protein which inhibits the claudin-16/19 comlex, increasing urinary excretion of calcium
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20
Q

How is calcium reabsorbed in the distal convoluted tubule (DCT, that is, NOT collecting duct)? What controls this?

A

Entirely through the transcellular route, via apical TRPV5 channels and basolateral Ca+2-ATPase and NCX.

TRPV5 channels are upregulated by PTH and calcitriol. NCX also upregulated by PTH

21
Q

How are Na+ and Ca+2 excretion linked? That is, should you be giving IV saline to a hyper or hypocalcemic patient?

A

Increasing Na+ reabsorption will result in parallel increases in calcium reabsorption. This is true in the proximal tubule (solvent drag drives paracellular reabsorption) and TALH (NKCC drives K+ for calcium reabsorption)

Thus, IV saline should be given to hypercalcemic patients so that they pee out their Na+ and Ca+2

22
Q

How do you treat calcium stones?

A

Thiazide diuretics. This illustrates the point that Na+ and Ca+2 reabsorption are not tightly linked in the distal convoluted tubule.

-> lack of Na+ reabsorption is associated with Ca+2 reabsorption, and hence less calcium in urine -> fewer stones

23
Q

What are the most common broad causes of hypercalcemia?

A

Primary hyperparathyroidism and malignancy

24
Q

What usually causes hyperparathyrodism?

A

Usually parathyroid adenoma or hyperplasia, less commonly parathyroidism carcinoma.

Can also rarely occur in the setting of multiple endocrine neoplasia

25
Q

What are the two ways malignancies can cause hypercalcemia?

A
  1. Local osteolytic hypercalcemia - tumor cells invade bone and produce cytokines stimulating osteoclastic bone resorption
  2. Humoral hypercalcemia - produce circulating PTHrP, or other cytokines
26
Q

What is PTHrP and will it be detected easily? What cancers is it associated with?

A

Parathyroid hormone-related peptide - NOT detected by normal PTH immunoassay

Associated with sQuamous cell cancers of lung, head, and neck (Q is next to P in the alphabet), as well as renal, bladder, breast, and ovarian cancers.

Think Q + urinary tract + BRCA

27
Q

How does vitamin D toxicity cause hypercalcemia (what mechanisms?) and who is it typically seen in?

A

Due to increased Ca+2 mobilization from bone as well as increased calcium absorption in GI tract (hard to overdo it in kidney)

Seen in patients treated with vitamin D: Renal failure (given vitamin D to combat chronically high PTH levels), and hypoparathyroidism (given vitamin D to increase Ca+2 levels)

28
Q

What is milk alkali syndrome?

A

Ingestion of large amount of milk and antacids which contain calcium carbonate can cause hypercalcemia

29
Q

What causes familial hypocalciuric hypercalcemia? What is it characterized by clinically?

A

Autosomal dominant disorder caused by defect calcium sensing receptor -> higher calcium levels required to suppress PTH release.

Causes hypocalciuria and mild hypercalcemia with elevated PTH levels. Usually asymptomatic.

30
Q

Why does hypercalcemia cause polyuria and increased Na+ excretion?

A

Ca+2 sensing receptor will inhibit the K+ channel in the TALH, which slows NKCC as well -> inhibits sodium reabsorption.

This destroys osmotic gradient of medulla -> cannot concentrate urine as well.

Also inhibits adenylate cyclase activity in collecting duct -> less ADH = nephrogenic diabetes insipidus

31
Q

What are the renal symptoms of hypercalcemia to remember?

A

Stones and thrones: Polyuria (with volume depletion and dehydration), nephrolithiasis (kidney stones), renal failure due to obstruction by stones and decreased RBF

32
Q

What are the other-than-renal symptoms of hypercalcemia to remember?

A

Metastatic calcification (of normal tissues, i.e. nephocalcinosis)

Psychiatric overtones: Coma, altered mental status

Groans: abdominal discomfort, nausea/vom

33
Q

How can tuberculosis affect blood calcium levels?

A

Like sarcoidosis and other granulomatous diseases, 1-alpha-hydroxylase of macrophages can cause hypercalcemia by increased conversion to calcitriol

34
Q

If a patient has normal or increased PTH vs decreased PTH with hypercalcemia what does that point to as most likely causes?

A

Normal or increased - hyperparathyroidism, such as primary parathyroidism or familial hypercalcemic hypocalciuria

Decreased - suppressed in hypercalcemia due to malignancy (PTHrP not picked up)

35
Q

Why does hypercalcemia tend to make hypercalcemia worse?

A

Polyuria leads to ECF volume depletion -> more Na+ and hence Ca+2 resorption in the proximal tubule

36
Q

What is the acute management strategy for hypercalcemia? Chronic?

A

Restoration of normal GFR via normal saline (ECF volume restoration)

Inhibit bone resorption with calcitonin + bisphosphonates

Chronic - treat underlying cause

37
Q

How do you correct total serum calcium levels to see if a patient is actually hypocalcemic in the setting of hypoalbuminemia?

A

Add 0.8 mg/dL for every 1 mg/dL decrease in serum albumin below 4 mg/dL

38
Q

What is the most common cause of hypoparathyroidism? What will this do to calcitriol levels?

A

Surgical removal of parathyroid gland

Decreases calcitriol levels (reduced conversion to 1,25-D3)

39
Q

What are causes of vitamin D deficiency and hence hypocalcemia?

A
  1. Decreased ingestion
  2. Decreased absorption - partial gastrectomy or intestinal bypass
  3. Deficiency of sunlight
  4. Deficiency of 25-D3, severe liver disease or anticonvulsant use (CYP inducers)
  5. Deficiency of calcitriol - advanced renal failure, hypoparathyroidism
40
Q

What is pseudohypoparathyrodism? What are characteristic features?

A

Resistance to effects of PTH - normal PTH levels with low calcium and high phosphate

Shortened 4th/5th digits, short stature

41
Q

In what situations can ionized calcium precipitate out and cause hypocalcemia?

A

Situations which release alot of phosphate into the blood, pushing formation of bone.

Advanced renal failure (phosphate retention), tumor lysis syndrome, rhabdomyolysis

42
Q

How can blood transfusions predispose to apparent hypocalcemia?

A

Blood tranfusions are citrated

-> citrate complexes with ionized calcium, decreasing its levels

43
Q

How can acute pancreatitis lead to hypocalcemia?

A

Fat necrosis due to inappropriate release and activation of pancreatic lipases will lead to calcium deposit onto the areas of lipolysis
-> dystrophic calcification lowering blood calcium levels

44
Q

What drugs cause hypocalcemia?

A

Calcitonin and bisphosphonates (obviously)

Foscarnet - CMV treatment and calcium chelator

45
Q

What is autosomal dominant hypocalcemia?

A

Activating mutation of calcium sensing receptor

  • > PTH is suppressed at lower calcium levels
  • > hypercalciuric hypocalcemia (opposite of other)
46
Q

What are the general features of hypocalcemia?

A

Neuromuscular irritability and tetany

-> can lead to lethargy, seizures, larnygospasm, and heart failure

47
Q

What are the “signs” associated with hypocalcemia?

A

Trousseau’s sign - carpal SPASM when BP cuff is inflated above systolic pressure for three minutes

Chvostek’s sign - TWITCHING of facial muscles when nerve is tapped at parotid gland

48
Q

What are the acute treatments of hypocalcemia? Longterm?

A

Acute: 1. Calcium supplements
2. Treat hypomagnesia if its suppression of PTH is the underlying cause

Longterm: calcium supplements and vitamin D

49
Q

Is calcium reabsorption in the distal convoluted tubule linked to sodium reabsorption? Talk about this with respect to thiazide diuretics.

A

Technically no. Despite PTH stimulating NCX and TRPV5, the primary stimulus for TRPV5 (apical calcium reabsorption) with thiazide use is not decreased levels of cytoplasmic sodium, but rather the hyperpolarization induced by increased Cl- lose on basolateral membrane and reduced Cl- uptake via NCC.

Pathophysiology - Urinary Tract (14 decks)

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