CONTENTS

• Components of the nephron:
  • Proximal tubule
  • Thick ascending loop of henle
  • Distal convoluted tubule
  • Cortical collecting duct (CCD)
• Renal handling of water
• Questions & discussion

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proximal tubule

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proximal tubule acid-base management 

reabsorption of bicarbonate

• The proximal tubule normally reabsorbs 80-90% of filtered bicarbonate.
  • ~70% occurs via the NHE3 channel. This is indirectly powered by the basolateral Na/K ATPase, which reduces intracellular Na+ and generates a negative intracellular charge. (32586924)
  • ~30% occurs via the apical H+-ATPase. (32586924)
• Regulation of bicarbonate reabsorption:
  • [1] Hypovolemia increases Na-HCO3 reabsorption.
  • [2] Hypokalemia increases bicarbonate reabsorption.
  • [3] Acidosis (either respiratory and/or metabolic) increased bicarbonate reabsorption.
• Proximal (type 2) RTA involves dysfunction of bicarbonate reabsorption, either:
  • (a) Impaired HCO3 transport across the basolateral membrane (NBCe1).
  • (b) Inhibition of carbonic anhydrase activity.

ammoniagenesis

• Ammoniagenesis is shown below. NH4+ synthesis also produces HCO3- which is secreted across the basolateral membrane via NBCe1 cotransporter (figure above).
• Regulation of ammoniagenesis:
  • [a] Intracellular pH.
  • [b] Inverse relationship between K+ and ammoniagenesis:
    • Hyperkalemia impairs ammoniagenesis (e.g., this is clinically relevant in type IV RTA).
    • Hypokalemia increases ammoniagenesis (e.g., this is one mechanism whereby hypokalemia serves to perpetuate metabolic alkalosis).

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thick ascending loop of henle

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acid-base physiology 

ammonia handling in the thick ascending loop of Henle

• Paracellular transport of NH4+ into the blood is driven by a lumen-positive voltage gradient.
• NH4+ can also enter into the apical membrane via:
  • NKCC2 channel (NH4+ can substitute for potassium, allowing it to be transported by the Na/K/2Cl cotransporter).
  • ROMK channel (the apical membrane K+ channel)
• The basolateral NBCn2 Na-HCO3 cotransporter may play a role in maintaining cellular pH.

bicarbonate reabsorption in the thick ascending loop of Henle

• Bicarbonate reabsorption occurs via a similar process as compared to the proximal convoluted tubule. However, it's powered by a flow of sodium (rather than a dedicated apical H+-ATPase channel, as in the proximal tubule).

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thick ascending loop of henle: magnesium physiology

• Major site of Mg reabsorption (~60%).
• Mg transport occurs between cells (paracellular) due to a lumen-positive electrical potential difference.
• The lumen-positive electrical potential difference is generated by the basolateral Na-K ATPase, NKCC2, ROMK, and the basolateral chloride channel.  Abnormalities of any of these channels may cause Bartter syndrome and hypomagnesemia.
• CASR (calcium-sensing receptor)
  • Activated by hypercalcemia and alkalosis.
  • Mechanistic effects:
    • Inhibits NKCC2 channel (similar to effect of furosemide).
    • Inhibits ROMK channel.
    • Inhibits claudins (thereby reducing paracellular Ca and Mg reabsorption).
  • Pathophysiological effects:
    • Salt wasting and volume contraction.
    • Reduced reabsorption of Ca and Mg.
• PTH (parathyroid hormone) increases magnesium reabsorption. (38372687)

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distal convoluted tubule

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distal convoluted tubule CaSR (calcium sensing receptor)

• Regulation of CaSR:
  • Activated by calcium.
  • Alkalosis.
• Effects:
  • Regulates paracellular cation permeability via claudin-14. Reduces paracellular Ca and Mg reabsorption.
  • Inhibits reabsorption of sodium by epithelial cell sodium channels.

magnesium physiology

• The distal convoluted tubule only reabsorbs ~10% of magnesium, but this is the final site where magnesium can be reabsorbed. Consequently, this site is essential to maintaining fine magnesium homeostasis.
• Magnesium reabsorption is transcellular, allowing for greater control.
• Entry of magnesium through the apical membrane is driven by a hyperpolarized lumen membrane potential, which is created by outward movement of potassium through the KV1.1 potassium channel.
• Magnesium transport across the basolateral membrane into the blood is driven by a sodium gradient generated by basolateral Na/K ATPase.  The basolateral Kir4.1 channel recycles potassium to prevent excessive intracellular potassium accumulation.
• Regulation: EGF (epidermal growth factor) stimulates TRPM6 activity, increasing Mg reabsorption.

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cortical collecting duct (CCD)

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⍺-intercalated cells generate (& reabsorb) bicarbonate

• Mechanism of H+ secretion:
  • H+ is secreted into the lumen by both the H+-ATPase and H/K-ATPase.
  • Intracellular hydroxide anions generate bicarbonate via intracellular carbonic anhydrase-II which is secreted across the basolateral membrane via AE1 (anion exchanger).
  • If there is residual bicarbonate in the lumen, H+ secretion will combine with luminal bicarbonate to generate CO2 – thereby facilitating reabsorption of luminal bicarbonate. (32586924)
• Regulation:
  • [1] This is indirectly regulated by reabsorption of Na by ENaC channels in the principal cells, which creates a lumen-negative voltage that pulls hydrogen ions into the lumen (discussed below).
  • [2] Hypokalemia increases H+ secretion, with an increase in H/K-ATPase activity.
• Distal (type 1) RTA involves dysfunction of the alpha-intercalated cells, either:
  • (a) Impaired hydrogen secretion by the H+-ATPase or H/K-ATPase.
  • (b) Increased H+ permeability (back-leak) of the luminal membrane.
• Potassium can exit the cell through channels in either the apical or basolateral membrane, which is regulated depending on the potassium balance.

principal cell

• Functions of principal cell:
  • [1] Na reabsorption.
  • [2] K secretion.
  • [3] Generation of lumen-negative voltage gradient (which drives H+ reabsorption via alpha-intercalated cells).
• Regulation: (factors promoting principal cell activity will promote metabolic alkalosis and hypokalemia)
  • [1] Aldosterone stimulates principal cell activity (increases production of the ENaC sodium channels  and the basolateral Na/K-ATPase). (Irwin 2023)
  • [2] Sodium delivery beyond the early distal tubule increases activity.
    • i) Loop and/or thiazide diuretics.
    • ii) Exogenous administration of sodium salts with poorly absorbed anions (e.g., phosphate, sulfate, penicillin).
  • Normally, these two factors are exquisitely balanced, to avoid excessive shifts in potassium and pH:
    • Volume depletion causes aldosterone stimulation and also increased proximal tubule sodium reabsorption.
    • Volume expansion causes aldosterone suppression and also reduced proximal tubule sodium.
  • Pathological shifts may occur if this balance is disrupted (e.g., primary hyperaldosteronism causes volume expansion which reduces proximal tubule sodium reabsorption – thereby causing a combination of aldosterone activity as well as high sodium delivery to the distal tubules). (32586924)
• Medications that block ENaC
  • Amiloride, triamterene.
  • Trimethoprim.
  • Pentamidine.
• Type IV RTA: aldosterone deficiency or resistance.
  • Reduced sodium reabsorption across the luminal membrane.
  • Decreased transepithelial voltage, which diminishes both:
    • (i) H+ secretion by the alpha-intercalated cells.
    • (ii) K+ secretion by the principal cells.
  • Hyperkalemia inhibits ammoniagenesis in the proximal tubule, further impairing the ability to excrete acid. (33367987)

β-intercalated cell secrete bicarbonate

• Beta-intercalated cells are involved in the renal response to metabolic alkalosis.
• Mechanism:
  • Basolateral H-ATPase absorbs H+ into the blood.
  • Hydroxy anions react with carbonic anhydrase-II to generate bicarbonate.  Bicarbonate is transported into the lumen via Pendrin.
• Regulation:
  • Generous distal delivery of Cl- is required for beta-intercalated cells to secrete major quantities of bicarbonate. (32586924)
  • Hypokalemia reduces pendrin activity (including transcriptional downregulation). (32586924)
  • Low luminal chloride concentrations impair HCO3- secretion via pendrin in patients with hypovolemia. (35525634)
• Cystic fibrosis with dysfunction of the CFTR gene may impair function of the beta-intercalated cells.

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renal handling of water

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proximal tubule

• Normally reabsorbs 65-80% of glomerular filtrate. (37822230)
• If more volume is reabsorbed in the proximal tubule, this is volume that isn't delivered to the remaining nephron (which may function in excretion of water).

diluting segments (thick ascending loop of Henle and distal convoluted tubule)

• Tubular fluid is diluted as it passes through the thick ascending limb of the loop of Henle and the distal convoluted tubule.
• Loop diuretics or thiazides may tend to cause hyponatremia by interfering with tubular dilution. However, loop diuretics also degrade the concentration gradient and cause production of diluted urine, limiting their ability to cause hyponatremia. (37822230)

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questions & discussion

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