Renal Calcium Regulation

Question 1

Intestinal phosphate absorption

Answer 1

Intestinal phosphate absorption is mediated by type IIb NaPi cotransporters, Npt2b, primarily in the duodenum and the jejunum

Active vitamin D (1,25(OH)2D) stimulates paracellular and transcellular intestinal absorption of calcium and the activity of Npt2b which leads to a net increase in absorption of BOTH intestinal calcium and phosphate.

Question 2

In an average healthy person, __% of serum calcium is filtered by the glomerulus

Answer 2

60%

The rest is not available for filtration, mostly being bound to albumin

Question 3

Proximal tubule calcium reabsorption

Answer 3

Question 4

Thick ascending loop of Henle calcium reabsorption

Answer 4

Question 5

Three steps of distal convoluted tubule calcium active transport

Answer 5

1. Ca²⁺ enters the apical membrane through the TRPV5 transporter
2. Ca²⁺ is shuttled across the cytosol by calbindin-D28k to the basolateral membrane
3. Ca²⁺ is extruded from the DCT cell through the sodium-calcium exchanger, NCX1 or a Ca²⁺-ATPase

Question 6

Distal tubule calcium reabsorption

Answer 6

Question 7

Role of the thick ascendling limb’s CaSR

Answer 7

When calcium levels are high, this CaSR inhibits ROMK, preventing the recycling of potassium and thus limiting the activity of the NKCC2.

The net result is decreased Ca²⁺ and Mg²⁺ reabsorption.

Question 8

Familial hypocalciuric hypercalcemia

Answer 8

These individuals have a LoF in CaSR. This results in disinhibited PTH production and disinhibition of ROMK in the thick ascending limb of the loop of Henle.

The net result is constant calcium mobilization and uninhibited renal calcium reabsorption, resulting in hypercalcemia and low urine calcium content.

Question 9

Thiazide diuretics for treatment of hypercelciuria and calcium-related nephrolithiasis

Answer 9

Thiazides block the activity of the NCC in the distal tubule and favor calcium reabsorption of TRPV5 in this segment.

However, the above is a minor effect in comparison to the increased proximal calcium reabsorption that thiazides induce simply by volume depletion and RAAS activation.

Question 10

Dietary methods for treating calcium-based nephrolithiasis

Answer 10

Hypercalciuria and associated nephrolithiasis can be avoided by reducing sodium intake and increasing water intake.

Decreased sodium intake will result in greater PCT sodium reabsorption, and when sodium is absorbed proximally calcium will follow. Increased fluid intake will activate vasopressin and result in more dilute urine, decreasing the concentration of urinary calcium.

Question 11

Proximal tubule phosphate handling

Answer 11

Question 12

1-α-hydroxylase regulation

Answer 12

• Expressed in the PCT
• Activity increased by PTH and hypocalcemia
• Inhibited by FGF23

Question 13

PTH effects on the kidney

Answer 13

• PCT:
  
  • Increased 1-α-hydroxylase expression
  • Decreased expression of Npt2a and Npt2c
• DCT:
  
  • Stimulates Ca²⁺ reabsorption via TRPV5

Question 14

Calcitriol effects on the kidney

Answer 14

Stimulates calcium reabsorption in the DCT via TRPV5

Question 15

FGF23 effects on the kidney

Answer 15

• PCT
  
  • Reduces the expression of Npt2a and Npt2c
  • Inhibits 1-α-hydroxylase

Question 16

Effects of hypercalcemia on the kidney

Answer 16

• Vasoconstriction of afferent arteriole and thus mildly decreased GFR
• Binding of CaSR in the TAL, resulting in ROMK inhibition and downstream inhibition of NKCC2. This dissipates the lumen positive charge and thus leads to inhibited calcium reabsorption and calciuria.
  
  • Of note, this inhibition of NKCC2 also leads to increased distal delivery of sodium and chloride and can affect the medullary gradient.
• Luminal calcium sensors promote aquaporin endocytosis in response to calciuria, which may cause nephrogenic diabetes insipidus. This prevents kidney stone formation, but causes water wasting.

Question 17

Renal calcium handling in chronic kidney disease

Answer 17

1. Reduction in 1-α-hydroxylase activity from loss of kidney mass, resulting in reduced calcitriol levels.
2. Hyperphosphatemia (begins incrementally when GFR falls below 60)
3. Secondary hyperparathyroidism (constantly secreted PTH due to hypocalcemia from calcitriol deficiency, hyperphosphatemia, and reduced expression of calcitriol/PTH/FGF2 receptors in the kidney)

Question 18

When secondary hyperparathyroidism develops, high serum levels of ___ are almost always present as well.

Answer 18

When secondary hyperparathyroidism develops, high serum levels of FGF23 are almost always present as well.

Question 19

Managing serum calcium in CKD

Answer 19

• Calcitriol supplementation (MUST be active calcitriol, D₂ and D₃ are insufficient due to lost 1-v-hydroxylae activity
• Dietary phosphate restriction and oral phosphate binders (such as calcium carbonate and calcium acetate) to reduce phosphate consumption and combat hyperphosphatemia
• Goals of therapy are to maintain bone strength/density and suppress PTH elevation

Question 20

Barterman’s syndrome is basically like always being on a ____, while Gitelman’s syndrome is basically like always being on a ____.

Answer 20

Barterman’s syndrome is basically like always being on a loop diuretic, while Gitelman’s syndrome is basically like always being on a thiazide diuretic

Because of this, they can be differentiated by urinary calcium level! It is low in Gitelman’s, but high in Barterman’s.

Remember, loops lose calcium.

Question 21

More detailed approach to hypercalcemia

Answer 21

Question 22

In secondary hyperparathyroidism, you do not see ___.

Answer 22

In secondary hyperparathyroidism, you do not see hypercalcemia!

Secondary hyperparathyroidism is an appropriate response

Question 23

Hypercalcemia symptom diagram

Answer 23

Question 24

If a patient presents with elevated calcium, high PTH, and very low urinary calcium in the context of intact renal function, what is the likely diagnosis?

Answer 24

FHH

Normally in this case, the CaSR of the TAL would appropriately shut down the NKCC1 and lead to hypercalciuria. However, in FHH, the CaSR is the primary lesion, and this mechanism cannot be activated.

This could also be a presentation of someone with primary hyperparathyroidism that is taking a thiazide diuretic, or someone with primary hyperparathyroidism and Gitelman’s syndrome.

DO NOT send these patients to surgery for parathyroidectomy.

Question 25

Bringing down the calcium level

Answer 25

Start w/ calcitonin for a few days while giving denosumab or bisphosphonates, as the latter two take a while to start working.

Question 26

Maintenance of a metabolic alkalosis

Answer 26

Question 27

“Trade-off” Hypothesis

Answer 27

In CKD, the GFR declines over time.

Increase in phosphate and decrease in calcium progressively causes PTH to rise and rise and rise to try and correct the phosphate and calcium levels.

Question 28

Metabolic acidosis in CKD

Answer 28

• Combined anion gap and non-anion gap
• AG: Sulfate and phosphate not excreted efficiently due to poor GFR
• non-AG: Reduced ammoniagenesis and H+ pumping, resulting in poor urine buffer capacity and inability to reabsorb bicarbonate as efficiently

Question 29

Osteodystrophy

Answer 29

Aka Hungry Bone Syndrome

The result of runaway PTH, seen often in tertiary hyperparathyroidism.

Abberrant, dysregulated multifocal bone demineralization all over the body. Also results in “tumors” of osteoclasts and marrow fibrosis.

Question 30

Tc⁹⁹ parathyroid scan

Answer 30

Similar to radioidine scan in the thyroid, but for parathyroids!

Can also be used to identify local parathyroid tumors.

Question 31

Chvostek’s sign

Answer 31

Sign of hypocalcemia

Tap two cm anteriorly and one cm inferiorly to the ear. This will produce a contraction of the muscles attached to the ipsilateral lips in a hypocalcemic patient.

Question 32

Medications for osteoporosis summary table

Answer 32