Regulation of calcium, phosphate and magnesium homeostasis Flashcards
What drives Ca2+ reabsorption in the DCT?
This is regulated by PTH levels.
In the distal tubule, where the voltage in the tubule lumen is electrically negative with respect to the blood, Ca++ reabsorption is entirely active because Ca++ is reabsorbed against its electrochemical gradient. Thus Ca++ reabsorption by the distal tubule is exclusively transcellular. Calcium enters the cell across the apical membrane by a Ca++-permeable ion channel (TRPV5). Inside the cell, Ca++ binds to calbindin-D28k. The calbindin-Ca++ complex carries Ca++ across the cell and delivers it to the basolateral membrane, where it is extruded from the cell primarily by the 3Na+/Ca++ antiporter (NCX1)
What affect does plasma [Ca2+] have on renal excretion/reabsorption of Ca2+?
Hypercalcemia activates the CaSR in the thick ascending limb of Henle’s loop, inhibiting Ca++ reabsorption in this segment, which results in an increase in urinary Ca++ excretion and thereby reduces plasma [Ca++]. Hypocalcemia has the opposite effect
How is Pi reabsorbed in the nephron?
What role do the kidneys play in regulating Ca2+ and PO4- levels in the plasma?
Regulate total body Ca++ and Pi by excreting the amount of Ca++ and Pi that is absorbed by the intestinal tract (normal bone remodeling results in no net addition of Ca++ and Pi to the bone or Ca++ and Pi release from the bone)
What drives Ca2+ reabsorption in the PCT?
Ca++ reabsorption by the proximal tubule occurs primarily via the paracellular pathway. This passive, paracellular reabsorption of Ca++ is driven by the lumen-positive transepithelial voltage across the second half of the proximal tubule and by a favorable concentration gradient of Ca++, both of which are established by transcellular sodium and water reabsorption in the first half of the proximal tubule.
What are the affects of PTH on the kidney?
PTH increases Ca++ reabsorption by the distal tubule of the kidney and stimulates the production of calcitriol in kidney (increases Ca++ absorption by the intestinal tract)
Why can loop diuretics lead to hypocalcemia?
They inhibit the Na+/K+/2Cl- transporter in TAL, which leads to less removal of (-) charge from urine, so there’s less driving force for Ca2+ and other (+) charged ions to diffuse across to blood via paracellular route.
They can be used to treat hypercalcemia.
What drives Ca2+ reabsorption in the loop of henle?
Ca++ reabsorption by the loop of Henle also occurs primarily via the paracellular pathway. Like the proximal tubule, Ca++ and Na+ reabsorption in the thick ascending limb parallel each other. These processes are parallel because of the significant component of Ca++ reabsorption that occurs via passive, paracellular reabsorption secondary to Na+ reabsorption that generates a lumen-positive transepithelial voltage
What effect does PTH have on renal handling of Ca2+?
Although PTH inhibits the reabsorption of NaCl and fluid (in order to increase phosphate excretion), and therefore Ca++ reabsorption by the proximal tubule, PTH stimulates Ca++reabsorption by the thick ascending limb of the loop of Henle and the distal tubule. Thus the net effect of PTH is to enhance renal Ca++ reabsorption
What affect does calcitriol have on the kidney?
Calcitriol enhances Ca++ reabsorption in the kidneys by increasing the expression of key Ca++ transport and binding proteins in the kidneys in order to increase blood Ca2+
Describe the amount of reabsorption of Ca2+ by the different areas of the nephron.
- The PCT reabsorbs […]% of Pi filtered by the glomerulus.
- By what means does it reabsorb Pi?
- The proximal tubule reabsorbs 80% of the Pi filtered by the glomerulus. The loop of Henle, distal tubule, and the collecting duct reabsorb negligible amounts of Pi. Therefore approximately 20% of the Pi filtered across the glomerular capillaries is excreted in the urine.
- Pi reabsorption by the proximal tubule occurs by a transcellular route (Figure 9-9). Pi uptake across the apical membrane of the proximal tubule occurs via two Na+-Pi symporters (IIa and IIc). Type IIa transports 3Na+ with one divalent Pi (HPO−24), and carries positive charge into the cell. Type IIc transports 2Na+ with one monovalent Pi (H2PO−4) and is electrically neutral. Pi exits across the basolateral membrane by a Pi-inorganic anion antiporter that has not been characterized.
Where is calcitriol produced?
Proximal tubule
Production of calcitriol in the kidney is stimulated by […] and […]
hypocalcemia and hypophosphatemia
Normally, […] of the filtered Ca++ is reabsorbed by the nephron.
99%
What would happen if blood Ca2+ and/or Pi were do decrease substantially?
Increased intestinal absorption, bone resorption and renal tubular reabsorption
In what forms can Ca2+ be found in the blood?
How does pH influence these ratios?
Acidemia increases the percentage of ionized Ca++ at the expense of Ca++bound to proteins, whereas alkalemia decreases the percentage of ionized Ca+
Complete image showing how much of each ion is secreted at each part of nephron. Additionally, what factors regulate the renal handling of these ions?
What is the bone - kidney - gut axis?
Relationship between the coordinated efforts of bone, kidney and gut to maintain extracellular fluid [Ca2+].
Low [Ca2+] in serum
- (+) bone to release Ca2+ and Pi
- (+) kidney to produce calcitriol
- (-) renal excretion Ca2+
- (+) renal excretion Pi
- calcitriol (+) intestinal absorption of Ca2+
Serum Ca2+ is tightly regulated. What are some consequences of hypocalcemia or hypercalcemia?
Calcium can exist in the blood in what forms?
Ionized (50%) –> biologically active / available
Complexed w/ protein (albumin, 40%)
As an anion complex (citrate, bicarb, phosphorous, 10%)
What % calcium is filtered by kidney?
Non-protein bound = 60%
What would happen to levels of ionized ca2+ in patient with hypoalbuminemia?
Ionized Ca2+ would increase
Ordering total calcium is a common lab test. What is the issue with ordering total calcium levels in person with hypoalbuminemia?
Underestimates ionized Ca++
What is the estimated relationship between calcium and albumin?
0.8mg Ca++ bound / g albumin
How does acidemia / alkalemia affect ca++ homeostasis?
What is the function of sclerostin?
Sclerositin inhibits Wnt signaling when present, thus inhibiting bone formation
Describe the regulation of PTH secretion.
Chief cells directly gauge the levels of Ca++ b/c they express CaSR GPCR, which couples to PLC and IP3 / Ca++ to inhibit PTH secretion. This is an exception to the rule, usually increased intracellular Ca++ leads to stimulation but in this case it tells the cell there’s too much ca++ in serum and inhibits PTH secretion.
What effect do increased levels of PTH have on the kidney?
- Increases levels of active Vit D (1,25 Dihydroxycholecalciferol)
- Increases Ca2+ reabsorption
- Decreases PO43- reabsorption
What effect do increased levels of PTH have on the intestines?
PTH does not act directly on the gut. Instead it increases the levels of active VitD which in turn increases Ca2+ and PO43- absorption
Describe the biosynthesis of VitD and the role of PTH in vitamin D synthesis.
In the skin, UV radiation converts cholesterol to 7-dehydrocholesterol. This is then converted to cholecalciferol in the plasma (VitD3). VitD3 is converted to 25 hydroxyVitD by the liver and that is converted to 1,25 dihydroxyVitD by the kidney. This final conversion to the active form is catalyzed by a cytochrome enzyme that is activated by PTH.
PTH increases serum phosphate by increasing release of mineral from bone and increasing phosphate absorption in the gut. High levels of phosphate can be toxic. Why don’t we inadvertently develop hyperphosphatemia from this normal pathway?
In the kidney, PTH inhibits the reabsorption of phosphate and sodium from the urine (lumen). It also stimulates the conversion of 25DHVitD to 1,25DHVitD.
Describe the effect of serum FGF23 on:
- PTH secretion
- 1,25DHVitD production
- The Kidneys
- The bones
- In general, FGF23 is working to decrease phosphate levels.
- Serum FGF23 inhibits secretion of PTH and production of 1,25DHVitD. FGF23 also causes the kidneys to resorb less phosphate, which can lead to hypophosphatemia, which can inhibit FGF23 in the bone. Additionally, 1,25DHVitD normally stimulates bone FGF23, so reduced levels of 1,25DHVitD will lead to reduced Bone FGF23.
What will be the body’s response to decreased Ca++?
Explain how PTH regulates urinary ca++ reabsorption and excretion.
Explain how PTH regulates urinary Pi reabsorption and excretion.
What is primary hyperparathyroidism?
What is secondary hyperparathyroidism?
1, 1
How can calcitonin be used as a potential osteoporosis therapy?
What are some of the important cellular actions of Pi?
True/false: phosphate levels are constant throughout life.
False - Normal Pi levels are higher in kids, lower in adults
How does FGF23 regulate Pi handling in the PT?
1 and 2 both right
1
