Lecture #9: Physiology: Transport of Potassium, Calcium, Magnesium and Phosphate

What percentage of total-body K⁺ is intracellular?

Approximately 98% of total-body K⁺ is intracellular, while only about 2% is in the extracellular fluid.

What is the normal plasma K⁺ concentration?

Plasma K⁺ is tightly maintained at approximately 3.5–5.0 mM.

Why must extracellular K⁺ be tightly regulated?

Extracellular K⁺ is critical for membrane potential; major changes can disturb skeletal and cardiac muscle excitation, contraction, conduction, and cardiac rhythm.

What are external and internal K⁺ balance?

External K⁺ balance is the relationship between K⁺ intake and excretion; internal K⁺ balance is the distribution of K⁺ between intracellular and extracellular compartments.

Which organ is primarily responsible for external K⁺ balance?

The kidney is responsible for most K⁺ excretion; the GI tract normally plays a minor role.

Why can a small shift of intracellular K⁺ greatly change plasma K⁺?

Because only about 2% of total-body K⁺ is extracellular; shifting as little as 1% of total-body K⁺ into or out of the ECF can change extracellular K⁺ by about 50%.

What happens to most K⁺ immediately after a dietary K⁺ load?

About 80% of an ingested K⁺ load temporarily shifts into cells, limiting the rise in plasma K⁺ until renal excretion increases.

Which hormones promote rapid K⁺ uptake into cells after a K⁺ load?

Insulin, epinephrine, and aldosterone promote movement of K⁺ from plasma into cells through stimulation of the Na⁺/K⁺-ATPase.

How does increased plasma K⁺ stimulate insulin?

Increased plasma K⁺ depolarizes pancreatic β cells, causing insulin release and promoting cellular K⁺ uptake.

How does increased plasma K⁺ stimulate aldosterone?

Increased plasma K⁺ depolarizes adrenal zona glomerulosa cells, directly stimulating aldosterone release.

How does acidemia affect plasma K⁺?

Acidemia promotes K⁺ movement out of cells and therefore tends to cause hyperkalemia.

Why does acidemia promote hyperkalemia?

Increased intracellular H⁺ impairs Na⁺/K⁺-ATPase and NKCC activity, reducing K⁺ influx, while decreased intracellular pH also reduces K⁺ binding to intracellular anions and promotes K⁺ efflux.

How does alkalemia affect plasma K⁺?

Alkalemia promotes cellular K⁺ uptake and therefore tends to cause hypokalemia.

Why does alkalemia promote hypokalemia?

Increased pH and HCO₃⁻ promote Na⁺ entry into cells, increasing intracellular Na⁺ and stimulating Na⁺/K⁺-ATPase activity, which drives K⁺ into cells.

How does hyperkalemia affect acid-base balance according to the lecture?

Hyperkalemia promotes intracellular alkalosis and extracellular acidosis.

How does hypokalemia affect acid-base balance according to the lecture?

Hypokalemia promotes intracellular acidosis and extracellular alkalosis.

What are the three processes determining renal K⁺ excretion?

Glomerular filtration, tubular reabsorption, and tubular secretion; urinary excretion = filtration − reabsorption + secretion.

How much K⁺ is normally filtered by the kidneys each day?

Approximately 800 mmol/day is filtered with a normal GFR and plasma K⁺.

How much of filtered K⁺ is normally excreted with a normal K⁺ intake?

Approximately 10–15% of the filtered K⁺ load is excreted to maintain balance.

How does renal K⁺ excretion change with low dietary K⁺ intake?

The kidney conserves K⁺ so only about 1–3% of the filtered load appears in urine.

How can K⁺ excretion exceed the filtered K⁺ load?

During chronic high K⁺ intake, distal tubular K⁺ secretion becomes so prominent that urinary K⁺ excretion can exceed 150% of the filtered load.

How much filtered K⁺ is reabsorbed in the proximal tubule?

Approximately 80% is reabsorbed isosmotically in the proximal tubule.

How is K⁺ reabsorbed in the proximal tubule?

Primarily by passive paracellular mechanisms: electrodiffusion and solvent drag accompanying water reabsorption.

How much filtered K⁺ is reabsorbed in the thick ascending limb?

Approximately 10% of the filtered K⁺ load is reabsorbed in the thick ascending limb.

What transporter mediates most transcellular K⁺ reabsorption in the thick ascending limb?

The apical NKCC2 Na⁺/K⁺/2Cl⁻ cotransporter.

What is the role of ROMK in the thick ascending limb?

ROMK recycles K⁺ back into the tubular lumen, supporting continued NKCC2 activity and the lumen-positive transepithelial voltage.

How do loop diuretics affect K⁺ handling in the thick ascending limb?

Loop diuretics inhibit NKCC2, reducing K⁺ reabsorption and eliminating the lumen-positive voltage that also drives paracellular cation reabsorption.

Which nephron segments determine final urinary K⁺ excretion?

The distal K⁺ secretory system: DCT, connecting tubule, cortical collecting tubule, and medullary collecting duct.

Which collecting-tubule cell primarily secretes K⁺?

Principal cells are primarily responsible for distal K⁺ secretion.

What are the three key requirements for K⁺ secretion by principal cells?

Basolateral Na⁺/K⁺-ATPase to load K⁺ into the cell, high and variable apical K⁺ permeability through ROMK, and an electrochemical gradient favoring K⁺ movement into the lumen.

How does ENaC activity promote K⁺ secretion?

Na⁺ entry through ENaC contributes to a lumen-negative electrical environment and promotes the electrochemical driving force for K⁺ secretion from principal cells.

How does amiloride affect K⁺ secretion?

Amiloride blocks ENaC, reducing the electrochemical gradient for K⁺ secretion and therefore acts as a K⁺-sparing diuretic.

What happens to renal K⁺ handling during K⁺ depletion?

Distal nephron segments increase K⁺ reabsorption, especially through H⁺/K⁺-ATPase activity in intercalated cells, conserving K⁺.

How can K⁺ depletion contribute to metabolic alkalosis?

K⁺ depletion increases H⁺/K⁺-ATPase density and activity, enhancing K⁺ reabsorption while increasing H⁺ secretion, contributing to hypokalemic alkalosis.

What factors stimulate distal K⁺ secretion?

Increased K⁺ intake, increased plasma K⁺, increased pH, mineralocorticoids, AVP, increased tubular flow, increased distal Na⁺ delivery, a more negative luminal voltage, and upstream diuretic use.

Why does increased distal tubular flow promote kaliuresis?

Increased flow is a potent stimulus for K⁺ secretion in the connecting and cortical collecting tubules and increases urinary K⁺ excretion.

How does aldosterone increase renal K⁺ excretion?

Aldosterone increases transcription of ENaC and ROMK and stimulates basolateral Na⁺/K⁺-ATPase activity in principal cells, increasing Na⁺ reabsorption and K⁺ secretion.

What regulates aldosterone secretion?

Angiotensin II and increased plasma K⁺ are major regulators; ACTH has a lesser effect.

How does RAAS connect Na⁺ balance to K⁺ balance?

RAAS generates angiotensin II, which stimulates aldosterone; aldosterone promotes distal Na⁺ reabsorption while simultaneously increasing K⁺ secretion.

What forms of plasma Ca²⁺ are filterable by the kidney?

Free ionized Ca²⁺ and diffusible Ca²⁺ complexes are filterable; protein-bound Ca²⁺, mainly bound to albumin, is not filterable.

How does acid-base status affect ionized plasma Ca²⁺?

H⁺ competes with Ca²⁺ for protein-binding sites; acidosis increases ionized Ca²⁺, whereas acute alkalosis decreases ionized Ca²⁺ and can mimic hypocalcemia.

How much filtered Ca²⁺ is reabsorbed by the kidney?

Approximately 99% of filtered Ca²⁺ is reabsorbed, leaving only about 1–3% for urinary excretion.

Where is filtered Ca²⁺ reabsorbed?

Approximately 65% in the proximal tubule, 25% in the thick ascending limb, and 8% in the distal convoluted tubule.

How is Ca²⁺ reabsorbed in the proximal tubule?

About 65% is reabsorbed by a paracellular, non-hormonally regulated process coupled to Na⁺ and water reabsorption.

How is Ca²⁺ reabsorbed in the thick ascending limb?

Most TAL Ca²⁺ reabsorption is passive and paracellular, driven by the lumen-positive transepithelial voltage generated by NKCC2 and ROMK activity.

Why is the distal convoluted tubule important for Ca²⁺ regulation?

Although it reabsorbs only about 8% of filtered Ca²⁺, it is the major regulatory site; Ca²⁺ enters through TRPV5/TRPV6 and exits basolaterally through Ca²⁺-ATPase and the Na⁺/Ca²⁺ exchanger.

Where does most renal Mg²⁺ reabsorption occur?

About 70% of filtered Mg²⁺ is reabsorbed in the thick ascending limb, compared with about 15% in the proximal tubule and 10% in the DCT.

How is Mg²⁺ reabsorbed in the thick ascending limb?

Primarily through the paracellular pathway driven by the lumen-positive voltage; claudin-16 and claudin-19 provide high paracellular Mg²⁺ permeability.

What is the major hormonal regulator of renal Mg²⁺ handling?

PTH is the most important hormone for Mg²⁺ regulation; AVP, glucagon, and calcitonin also increase Mg²⁺ reabsorption in the TAL.

Where is most filtered phosphate reabsorbed?

The proximal tubule reabsorbs approximately 80–95% of filtered phosphate through transcellular Na⁺/phosphate cotransporters.

What major factors regulate renal phosphate reabsorption?

PTH, dopamine, 1,25-dihydroxyvitamin D, phosphatonins such as FGF23, glucocorticoids, and acid-base balance regulate proximal tubular phosphate transport.