Loop diuretics, NKCC2 and urine concentration
Loop diuretics block NKCC2, a transporter, in the thick ascending limb (the thick segment of the hairpin-shaped loop of Henle that carries fluid back up).
Remember
Loop diuretics block NKCC2 in the thick ascending limb, so they are the most powerful diuretics, and the same block blunts the salty gradient of the inner kidney (the medulla), so the kidney can no longer concentrate urine well.
Loop diuretics, such as furosemide and bumetanide, act on the thick ascending limb. Their target is NKCC2, the Na+/K+/2Cl- cotransporter, a protein in the cell membrane that carries one sodium, one potassium and two chloride ions together. That segment reabsorbs around a quarter of the filtered sodium, so blocking it leaves a large amount of sodium and water lost in the urine, and loop diuretics are the most powerful class of diuretic.
The same segment is impermeable to water, so when it pumps salt out, the water cannot follow. The salt that stays behind in the surrounding tissue makes the medulla very salty; the medulla is the inner region of the kidney. The medullary gradient is the steep rise in saltiness as you move towards the tip of the medulla. When antidiuretic hormone (ADH, which makes the kidney hold on to water) is present, the gradient draws water out of the collecting duct, at the end of the nephron, so concentrated urine can be made. Loop diuretics blunt the gradient, so less water is reclaimed and the urine is less concentrated.
Thiazide diuretics are the classic confusion. Thiazides also block a sodium-chloride cotransporter, but a different one, NCC, which carries only sodium and chloride. It sits in the distal convoluted tubule (the part that comes after the loop of Henle), which reabsorbs only about 5% of filtered sodium, so thiazides are moderate-potency diuretics.
Key facts
- Target
- NKCC2, the Na+/K+/2Cl- cotransporter, found in the thick ascending limb, part of the loop of Henle.
- Examples
- furosemide and bumetanide.
- Potency
- the thick ascending limb handles around a quarter of the filtered sodium, so loop diuretics are the most powerful class.
- Concentrating ability
- the segment is impermeable to water and builds the medullary gradient, so blocking it weakens the gradient and the kidney concentrates urine less well.
- Electrolytes
- calcium and magnesium are lost as well as sodium and potassium, so low potassium (hypokalaemia), low calcium (hypocalcaemia) and low magnesium (hypomagnesaemia) can follow.
- Main use
- relieving fluid overload in heart failure and pulmonary oedema (fluid in the lungs).
Exam traps
- Thiazide diuretics are easily mistaken for loop diuretics because the names of their transporters sound alike, but thiazides block the sodium-chloride cotransporter further along, in the distal convoluted tubule, and they are less powerful than loop diuretics.
- Blocking NKCC2 in the descending limb of the loop of Henle (the part of the loop that is permeable to water) is not where loop diuretics act, because their site is the thick ascending limb, which reabsorbs sodium but is impermeable to water.
- Loop diuretics do not increase water reabsorption in the thick ascending limb, because that segment is impermeable to water, so no water moves there to increase; water is reclaimed later in the collecting duct under ADH.
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