RENAL

Calcium

Overview

In this module, we'll go over common questions about calcium handling in the proximal tubule, thick ascending loop of Henle, distal tubule, and collecting duct.

Thick Ascending Loop of Henle

Why do loop diuretics increase urinary excretion of calcium and magnesium?

In the thick ascending loop of Henle (TAL), there is normally paracellular transport of calcium and magnesium from the lumen of the TAL to the interstitium. This is because of a positive lumen potential created when potassium leaks out of the TAL and back into the lumen via K+ leak channels. At the same time, chloride ions move from the lumen, into the TAL, and out to the interstitium.

Loop diuretics, such as furosemide, work by competing for the chloride site of the NKCC2 channel found on the luminal side of the TAL. This decreases NaCl reabsorption, which reduces the positive lumen potential that was responsible for driving paracellular transport of calcium and magnesium (1). Remember, the positive lumen potential of the nephron at the TAL was a result of chloride moving from the lumen to the interstitium AND potassium leaking back into the lumen.

Here's a video to provide a visual explanation of what is happening to calcium at the TAL with loop diuretics:

Distal Convoluted Tubule

About 10% of calcium will be reabsorbed in the distal convoluted tubule (DCT).

Why do thiazide diuretics increase calcium reabsorption?

In the distal convoluted tubule, calcium reabsorption is uncoupled from sodium reabsorption. This means that thiazide diuretics, which affect the Na-Cl co-transporter (NCC), will not affect calcium reabsorption in the same way. There are actually two explanations for why thiazide diuretics increase calcium reabsorption, and the parts of the nephron involved are the proximal convoluted tubule (PCT) and DCT. Let's break it down:

Mechanism 1: Increased calcium reabsorption in PCT & TAL because of thiazide use

  1. Thiazide use inhibits NCC in the DCT. As a result, your body gets a little bit volume depleted because there is less Na reabsorption (and thus, less water follows).
  2. Because your body has become volume depleted, the PCT and TAL "activate" to compensate for the volume depletion and reabsorb more Na than before.
  3. In the PCT and TAL, Na reabsorption IS coupled with Ca reabsorption and so more Ca is reabsorbed paracellularly at the PCT and TAL.

Mechanism 2: Increased calcium reabsorption in DCT because of thiazide use

  1. Again, thiazide use inhibits NCC in the DCT. As a result, less Na is concentrated within the cells of the DCT.
  2. The decreased Na concentration in the cells of the DCT makes the Na-Ca antiporter (NCX1) found in the basolateral membrane of the DCT cells work harder. This NCX1 antiporter pumps 3 Na into the DCT cells while simultaneously pumping 1 Ca out into the interstitium.
  3. The increased activity of NCX1 encourages Ca to move from the lumen into the cells of the DCT (via TRPV5 channels) and then gets pushed out to the interstitium via the NCX1 antiporter. Thus, more Ca is reabsorbed at the DCT.

Here's a video to provide a visual explanation of what is happening to calcium at the PCT, TAL, and DCT with thiazide diuretics: