CONTENTS
- Proximal tubule
- Thick ascending loop of henle
- Distal convoluted tubule
- Cortical collecting duct (CCD)
- Questions & discussion
proximal tubule acid-base management
reabsorption of bicarbonate
- The proximal tubule normally reabsorbs 80% of filtered bicarbonate.
- 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.
![](https://i0.wp.com/emcrit.org/wp-content/uploads/2024/07/proxtubule.jpg?resize=450%2C326&ssl=1)
CA = carbonic anhydrase.
NBCe1 = Na/HCO3 cotransporter.
ammoniagenesis
![](https://i0.wp.com/emcrit.org/wp-content/uploads/2024/07/ammoniaprox.jpg?resize=450%2C378&ssl=1)
NHE3 = apical sodium hydrogen exchanger 3.
acid-base physiology
bicarbonate reabsorption
- 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).
![](https://i0.wp.com/emcrit.org/wp-content/uploads/2024/07/tal.jpg?resize=450%2C326&ssl=1)
NBCe1 = Na/HCO3/CO3 cotransporter.
AE1 = anion exchanger 1.
ammonia handling
- Lumen-positive voltage drives paracellular transport of NH4+ into the blood.
- NH4+ can also enter into the apical membrane via:
- NH4+ can substitute for potassium, allowing it to be transported by the Na/K/2Cl cotransporter.
- Apical membrane K+ channel (ROMK).
- The basolateral NBCn2 Na-HCO3 cotransporter may play a role in maintaining cellular pH.
![](https://i0.wp.com/emcrit.org/wp-content/uploads/2024/07/ammoniatal.jpg?resize=450%2C378&ssl=1)
NBCn2 = Na/bicarbonate cotransporter.
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) regulates paracellular cation permeability via claudin-14.
- Hypercalcemia –> activation of CASR –> reduces paracellular Ca and Mg reabsorption.
- PTH (parathyroid hormone) increases magnesium reabsorption. (38372687)
![](https://i0.wp.com/emcrit.org/wp-content/uploads/2019/08/mgphys1.jpg?resize=500%2C338&ssl=1)
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.
![](https://i0.wp.com/emcrit.org/wp-content/uploads/2019/08/mgphys2.jpg?resize=500%2C314&ssl=1)
acid base physiology
alpha-intercalated cells generate 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 which is secreted across the basolateral membrane via AE1 (anion exchanger).
- Regulation: 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).
- 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.
![](https://i0.wp.com/emcrit.org/wp-content/uploads/2024/07/intercalated.jpg?resize=450%2C326&ssl=1)
principal cell
- 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)
![](https://i0.wp.com/emcrit.org/wp-content/uploads/2024/07/principle.jpg?resize=400%2C379&ssl=1)
beta-intercalated cell secrete bicarbonate, absorb acid
- 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.
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References
- 33367987 Palmer BF, Kelepouris E, Clegg DJ. Renal Tubular Acidosis and Management Strategies: A Narrative Review. Adv Ther. 2021 Feb;38(2):949-968. doi: 10.1007/s12325-020-01587-5 [PubMed]
- 36872194 Rosner MH, Ha N, Palmer BF, Perazella MA. Acquired Disorders of Hypomagnesemia. Mayo Clin Proc. 2023 Apr;98(4):581-596. doi: 10.1016/j.mayocp.2022.12.002 [PubMed]
- 38372687 Adomako EA, Yu ASL. Magnesium Disorders: Core Curriculum 2024. Am J Kidney Dis. 2024 Jun;83(6):803-815. doi: 10.1053/j.ajkd.2023.10.017 [PubMed]