Renal Calcium Regulation Flashcards
Intestinal phosphate absorption
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.
In an average healthy person, __% of serum calcium is filtered by the glomerulus
60%
The rest is not available for filtration, mostly being bound to albumin
Proximal tubule calcium reabsorption
Thick ascending loop of Henle calcium reabsorption
Three steps of distal convoluted tubule calcium active transport
- Ca2+ enters the apical membrane through the TRPV5 transporter
- Ca2+ is shuttled across the cytosol by calbindin-D28k to the basolateral membrane
- Ca2+ is extruded from the DCT cell through the sodium-calcium exchanger, NCX1 or a Ca2+-ATPase
Distal tubule calcium reabsorption
Role of the thick ascendling limb’s CaSR
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.
Familial hypocalciuric hypercalcemia
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.
Thiazide diuretics for treatment of hypercelciuria and calcium-related nephrolithiasis
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.
Dietary methods for treating calcium-based nephrolithiasis
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.
Proximal tubule phosphate handling
1-α-hydroxylase regulation
- Expressed in the PCT
- Activity increased by PTH and hypocalcemia
- Inhibited by FGF23
PTH effects on the kidney
- PCT:
- Increased 1-α-hydroxylase expression
- Decreased expression of Npt2a and Npt2c
- DCT:
- Stimulates Ca2+ reabsorption via TRPV5
Calcitriol effects on the kidney
Stimulates calcium reabsorption in the DCT via TRPV5
FGF23 effects on the kidney
- PCT
- Reduces the expression of Npt2a and Npt2c
- Inhibits 1-α-hydroxylase
Effects of hypercalcemia on the kidney
- 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.
Renal calcium handling in chronic kidney disease
- Reduction in 1-α-hydroxylase activity from loss of kidney mass, resulting in reduced calcitriol levels.
- Hyperphosphatemia (begins incrementally when GFR falls below 60)
- Secondary hyperparathyroidism (constantly secreted PTH due to hypocalcemia from calcitriol deficiency, hyperphosphatemia, and reduced expression of calcitriol/PTH/FGF2 receptors in the kidney)
When secondary hyperparathyroidism develops, high serum levels of ___ are almost always present as well.
When secondary hyperparathyroidism develops, high serum levels of FGF23 are almost always present as well.
Managing serum calcium in CKD
- 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
Barterman’s syndrome is basically like always being on a ____, while Gitelman’s syndrome is basically like always being on a ____.
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.
More detailed approach to hypercalcemia
In secondary hyperparathyroidism, you do not see ___.
In secondary hyperparathyroidism, you do not see hypercalcemia!
Secondary hyperparathyroidism is an appropriate response
Hypercalcemia symptom diagram
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?
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.
