Renal Potassium Regulation

Potassium is the main intracellular cation in all cells and is distributed unevenly between the intracellular fluid (98%) and extracellular fluid (2%). This large disparity is necessary for maintaining the resting membrane potential of cells, and explains why K+ balance is tightly regulated. The GI tract secretes 5%–10% of the absorbed K+ daily; however, the kidneys are responsible for 90%–95% of the overall K+ regulation. While most of the K+ is reabsorbed in the proximal tubules, the majority of regulation occurs in the principal and α-intercalated cells of the collecting ducts. The most important regulatory mechanisms include aldosterone, plasma K+ concentration, distal urinary flow rate, and the distal delivery of Na+ and water. Hyperkalemia and hypokalemia can result when K+ regulation is abnormal.

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Overview

Introduction

Potassium distribution:

  • Intracellular fluid (ICF) space: 98%
    • Maintained by Na+/K+ ATPase (requires energy)
    • Critical for nerve conduction and muscle contraction
  • Extracellular fluid (ECF) space: 2%
    • Serum K+ levels represent the K+ in the ECF only. 
    • Normal range: 3.5–5.2 mEq/L

Mechanisms of K+ balance:

  • Intake through the diet
  • GI losses (5%–10%)
  • Renal losses (90%–95%)
  • Transcellular K+ shift: 
    • Redistribution between the ICF and ECF
    • Prevents excessive ↑ in ECF K+ concentration
    • K+ shifts primarily from the ECF into muscle and liver cells.

Renal processes to regulate water, electrolytes, and waste

  • Filtration: Plasma is filtered in the glomerular capillaries, creating a filtrate that passes through the renal tubules.
  • Reabsorption: Required solutes and water are reabsorbed from the tubule lumen back into the blood.
  • Secretion: Waste products are intentionally secreted into the lumen.
  • Excretion: Filtrate remaining in the tubules is excreted as urine.
Primary renal functions

Primary renal functions

Image by Lecturio. License: CC BY-NC-SA 4.0

Nephron anatomy review

Nephrons are the functional units of the kidney.

Nephron segments (in order through which the filtrate flows):

  • Bowman’s capsule
  • Proximal convoluted tubule
  • Loop of Henle:
    • Thin descending limb
    • Thin ascending limb
    • Thick ascending limb
  • Distal convoluted tubule
  • Collecting duct

Types of nephrons:

  • Cortical (or superficial): Loops of Henle only penetrate as deep as the outer medulla.
  • Juxtamedullary: 
    • Nephrons whose loops penetrate all the way into the inner medulla
    • Allow for ↑ concentration of the urine (due to ↑ osmolality in the inner medulla)
Nephron anatomy

Nephron anatomy

Image by Lecturio. License: CC BY-NC-SA 4.0

Potassium Regulation in the Glomerulus, Proximal Tubule, and Loop of Henle

Glomerulus

  • K+ is freely filtered from the blood passing through the glomerular capillaries into Bowman’s space.
  • No regulatory actions occur in the glomerulus.
Early nephron segments

Early nephron segments (glomerulus and proximal tubule)

Image by Lecturio. License: CC BY-NC-SA 4.0

Proximal tubule

Cells of the proximal convoluted tubule have the most absorptive capabilities in the entire nephron. All of the glucose, amino acids, and about 65% of Na+ and water are reabsorbed in the proximal tubule, in addition to a majority of the K+.

  • About 65%–70% of the filtered K+ is reabsorbed.
  • Reabsorption is paracellular (between cells) rather than transcellular (which is an active process that requires energy).
  • Passive paracellular transport occurs via:
    • Diffusion
    • Solvent drag

Remember the 3 Ps:

  • Proximal tubule
  • Passive transport
  • Paracellular
Paracellular transport of potassium

Paracellular transport of K+ in the proximal tubule

Image by Lecturio. License: CC BY-NC-SA 4.0

Thick ascending limb of the loop of Henle

About 10%–25% of the filtered K+ is reabsorbed in the loop of Henle. Reabsorption involves the following 2 transport proteins on the luminal side:

  • NKCC2 multiporter:
    • Active transport (requires energy from basolateral Na+/K+ ATPase)
    • Transports the following into the cell from the tubule lumen:
      • 1 Na+
      • 1 K+
      • 2 Cl 
    • Maintains electrical neutrality by moving 2 positively charged and 2 negatively charged ions together, all in the same direction
    • Loop diuretics (furosemide, torsemide, bumetanide) inhibit NKCC2 → retains Na+, K+, and Cl in the lumen.
  • ROMK (renal outer medullary potassium) channel:
    • Allows K+ to exit the cell into the tubular lumen
    • A regulated channel for passive transport
    • Stimulated by low intracellular ATP: Na+/K+ ATPase has utilized ATP to bring K+ into the cell, which needs to be excreted.
    • Important for the recycling of K+ to allow NKCC2 to continue its function:
      • There is a much higher concentration of Na+ than K+ in the tubule lumen.
      • Recycling K+ into the tubule lumen allows NKCC2 to keep bringing more Na+ into the cells.
Potassium movement at the loop of henle

K+ movement at the thick ascending limb of the loop of Henle

Image by Lecturio. License: CC BY-NC-SA 4.0

Potassium Regulation in the Collecting Ducts

Although the largest amounts of K+ are reabsorbed in the proximal convoluted tubules, the primary sites of significant K+ regulation occur in the collecting ducts, within the principal and α-intercalated cells.

Principal cells

  • Located in the cortical collecting ducts 
  • Basolateral side: 
    • Na+/K+ATPase: 3 Na+ move out of the cell, 2 K+ move into the cell
  • Luminal side: 
    • Epithelial sodium channel (ENaC): 1 Na+ moves into cell.
      • For each Na+ that moves into the cell, a Cl is left behind in the tubular lumen.
      • Creates an electrical gradient where the luminal side is more negative
    • ROMK channel: A K+ moves out of the cell.
  • K+ moves into the principal cells from the capillaries through the Na+/K+ATPase (active transport) and out into the lumen through the ROMK channels (passive regulated transport).
Potassium movement in the principal cell

Potassium movement in the principal cell

Image by Lecturio. License: CC BY-NC-SA 4.0

Excretion of K+ from the principal cells

Potassium exits into the lumen through the ROMK channels, which are controlled by factors that affect passive transport:

  • Diffusion gradient: 
    • ↑ Intracellular K+ (K+ is primarily located in the ICF due to the Na+/K+ATPase)
    • ↓ Luminal K+ 
    • Favors efflux of K+ into the lumen
  • Electrical gradient:
    • In the tubular lumen, every Na+ is accompanied by a Cl.
    • When a Na ion moves through the ENaC channel, the accompanying chloride ion remains in the tubular lumen and generates the electrical gradient.
    • Increasingly negative luminal charge attracts K+.
    • ↑ ENaC channel activity→ ↑ electronegativity of tubular lumen→ ↑ affinity for K+ to move into tubular lumen through the ROMK channel
  • K+ permeability of the luminal membrane:
    • ROMK channels can open and close.
    • ROMK channels open when the intracellular ATP is low.

Regulation of K+ excretion from the principal cells

There are 4 primary factors that regulate K+ excretion at the level of the principal cells:

  • Aldosterone: 
    • Stimulates basolateral Na+/K+ATPase to bring more K+ into the cells
    • ↑ Number of open luminal channels:
      • ENaC channels AND
      • ROMK channels
    • End effect: ↑ K+ excretion 
  • Increasing plasma K+ concentration (same as aldosterone):
    • Stimulates basolateral Na+/K+ATPase
    • ↑ Number of open luminal channels:
      • ENaC channels AND
      • ROMK channels
    • End effect: ↑ K+ excretion
  • Distal tubular flow rate:
    • High flow (e.g., polyuria):
      • K+ secreted by the ROMK channel is quickly moved to the next part of the nephron.
      • The concentration gradient favors diffusion of K+ into the tubular fluid.
      • End effect: ↑ urine flow = ↑ K+ excretion (and ↓ serum K+)
    • Low flow (e.g., oliguria):
      • Tubular K+ remains closer to the ROMK channel after secretion.
      • There is less of a concentration gradient for the diffusion of K+ through the ROMK channel. 
      • End effect: ↓ urine flow = ↓ K+ excretion (and ↑ serum K+)
  • Distal Na+ delivery:
    • High distal Na+ delivery: 
      • More Na+ is moving into the cell via the ENaC channel.
      • = More Cl left behind in tubular lumen
      • = Greater electronegative tubular lumen
      • = Higher electrical gradient for K+ secretion through the ROMK channel
    • Low distal Na+ delivery: 
      • Less Na+ enters the cell via the ENaC channel.
      • = Less Cl left behind in tubular lumen
      • = Less electronegative tubular lumen
      • = Lower electrical gradient for K+ secretion through the ROMK channel
    • Loop and thiazide diuretics block the NKCC2 channels in the loop of Henle:
      • Allow for ↑ Na+ delivery to the more distal collecting ducts
      • Represents the mechanism for hypokalemia due to these diuretics.

α-intercalated cells

α-Intercalated cells allow for the fine-tuning of urinary K+ excretion.

  • Located in the collecting duct
  • H+/K+ ATPase on the luminal side:
    • 1 H+ out of the cell, 1 K+ into the cell
    • Active transport protein (requires ATP for energy)
  • K+ conservation mechanism: enables urinary K+ excretion of < 15 mmol/day in hypokalemic states due to nonrenal losses
Potassium regulation at the α-intercalated cell

Potassium regulation at the α-intercalated cell

Image by Lecturio. License: CC BY-NC-SA 4.0

Response to Ingested K+

Normal response to ingested K+

A normal Western diet contains approximately 40–120 mmol K+ per day. The normal response to ingested K+ occurs as follows:

  1. Gut absorbs dietary K+ into the bloodstream.
  2. Transcellular shifts:
    • Potassium ions shift primarily into the muscle and liver cells.
    • Prevents excessive increases in ECF K+ concentration
    • Promoted by insulin and β2-adrenergic activity, which both ↑ the activity of Na+/K+ ATPase
  3. Increased ECF K+ concentration triggers mechanisms for renal K+ excretion
    • In the principal cells:
      • Basolateral Na+/K+ ATPase is stimulated.
      • ↑ Number of open luminal ENaC and ROMK channels
    • Aldosterone production is stimulated:
      • Further stimulates Na+/K+ ATPase
      • Further ↑ in luminal ENaC and ROMK channels in principal cells
  4. Transcellular shifting into the muscle/liver cells gradually reverses.
  5. The remainder of the ingested K+ load is renally excreted.
Table: Potassium content of selected foods
Food Portion size mmol K+
Avocado 1, medium 38
Sirloin steak 8 oz 23
Orange juice 8 oz 12
Potato, baked 7 oz 22
Raisins ⅔ cup 19
Tomato paste ½ cup 31
Banana 1, medium 12

Abnormalities

  • Kidneys effectively regulate K+ excretion (especially at the α-intercalated cells).
  • Both hypo- and hyperkalemia due to decreased or increased intake is unlikely.
  • Exception: states of chronic malnutrition (e.g., alcoholism)

Clinical Relevance

Renal causes of hypokalemia

Several common causes of increased urinary losses of K+ leading to hypokalemia include:

  • Diuretic use: Diuretics can affect K+ levels in several ways. Diuretics acting proximally to the collecting ducts, including loop and thiazide diuretics, increase distal Na+ delivery, which stimulates K+ excretion. Volume depletion as a result of the diuretics can also activate the RAAS, increasing aldosterone secretion, which in turn increases K+ excretion.
  • A primary increase in mineralocorticoid activity: most often due to an aldosterone-producing adrenal adenoma or bilateral adrenal hyperplasia. Patients with increased mineralocorticoid activity usually have accompanying hypertension.
  • Non-reabsorbable anions: The presence of non-reabsorbable anions in the lumen makes it more negative, increasing the amount of Na+ retained all the way into the collecting ducts. The increased distal delivery of Na+ and water then leads to an increased exchange of Na+ for K+ at the principal cells, leading to hypokalemia. Non-reabsorbable anions include bicarbonate (increased with vomiting and proximal renal tubular acidosis), β-hydroxybutyrate (increased in ketoacidosis), and hippurate (increased with toluene use/glue sniffing). 
  • Diabetic ketoacidosis: There are 3 different mechanisms that contribute to hypokalemia in diabetic ketoacidosis.
    1. A glucose-driven osmotic diuresis results in increased distal Na+ and water delivery.
    2. Hypovolemia induces hyperaldosteronism.
    3. Production of the non-reabsorbable β-hydroxybutyrate anion is increased. 
  • Less common causes: polyuria (due to psychogenic polydipsia), renal tubular acidosis, hypomagnesemia, use of amphotericin B, and low-calorie diets. Mutations in tubular-transport proteins, including Liddle’s syndrome, Bartter syndrome, and Gitelman syndrome, can cause or contribute to hypokalemia.

Renal causes of hyperkalemia

Several common causes of reduced urinary losses of K+ leading to hyperkalemia include:

  • Reduced aldosterone secretion: Any condition that reduces aldosterone secretion will reduce K+ excretion. Causes of reduced aldosterone secretion may include both hyporeninemic hypoaldosteronism (situations of volume overload, diabetic nephropathy, autonomic neuropathy, and some systemic diseases) and hyperreninemic hypoaldosteronism (including primary adrenal insufficiency, chronic heparin use, and several congenital anomalies). Several drugs can also be causative, including ACE inhibitors, NSAIDs, calcineurin inhibitors, and heparin.
  • Reduced response to aldosterone: caused by potassium-sparing diuretics like aldosterone antagonists (e.g., spironolactone, eplerenone) and ENaC antagonists (e.g., amiloride and triamterene); voltage-dependent renal tubular acidosis (due to impaired sodium reabsorption in the principal cells); and pseudohypoaldosteronism (a rare genetic disorder causing aldosterone resistance).
  • Reduced distal Na+ and water delivery: results from effective arterial blood-volume depletion, including GI and renal losses, heart failure, and cirrhosis. When distal delivery of Na and water decreases, less Na+ is reabsorbed in exchange for K+; therefore, less K+ is excreted.
  • Acute and CKD: As the number of functioning nephrons decreases, the ability of the kidney to excrete K+ decreases. Potassium excretion is typically maintained as long as the patient is able to respond to aldosterone, and the delivery of Na+ and water is maintained. Hyperkalemia tends to occur in patients who are oliguric or have additional problems that may contribute to hyperkalemia.

References

  1. Mount, D.B. (2020). Causes and evaluation of hyperkalemia in adults. UpToDate. Retrieved March 9, 2021, from https://www.uptodate.com/contents/causes-and-evaluation-of-hyperkalemia-in-adults
  2. Mount, D.B. (2020). Causes of hypokalemia in adults. UpToDate. Retrieved March 1, 2021, from https://www.uptodate.com/contents/causes-of-hypokalemia-in-adults

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