Lecture #14: Physiology: Transport of Acids and Bases

What organs are primarily responsible for acid-base balance?

The lungs and kidneys. The lungs regulate CO₂, while the kidneys regulate H⁺ secretion, HCO₃⁻ reabsorption/production, and excretion of nonvolatile acids.

What is the normal arterial pH range?

7.37–7.42.

What is the largest source of acid production in the body?

CO₂ production from oxidation of carbohydrates, fats, and most amino acids. The lungs eliminate this CO₂ across the alveolar-capillary barrier.

What are volatile acids?

Acids derived directly from hydration of CO₂ through the reaction CO₂ + H₂O ⇄ H₂CO₃ ⇄ HCO₃⁻ + H⁺.

What are nonvolatile acids?

Acids not derived directly from CO₂ hydration; they must ultimately be neutralized and excreted by the kidneys. H₂PO₄⁻ is an example.

What is the major buffering system in the body?

The CO₂/HCO₃⁻ buffering system.

What is the major buffer system synthesized by the kidney?

The NH₃/NH₄⁺ buffer system.

Which metabolic processes generate nonvolatile acids?

Oxidation of sulfur-containing amino acids, phosphorus-containing compounds, and cationic amino acids; production of nonmetabolizable organic acids; and incomplete oxidation of carbohydrates and fats producing lactic acid or ketoacids.

Which metabolic processes generate nonvolatile bases?

Oxidation of anionic amino acids such as glutamate and aspartate and oxidation of organic anions such as lactate and acetate generate HCO₃⁻.

Why must the kidneys reabsorb virtually all filtered HCO₃⁻?

About 4320 mmol of HCO₃⁻ is filtered daily. Failure to retrieve it would create an enormous blood acid load and cause catastrophic metabolic acidosis.

What is the approximate daily nonvolatile acid load that must be excreted?

About 70 mmol/day from metabolism, diet, and intestinal losses.

Why can't the kidney excrete the daily acid load as free H⁺ alone?

Excreting 70 mmol/day as free H⁺ would require a urinary pH of about 1.3, but the minimum achievable urinary pH is approximately 4.4. H⁺ must therefore be buffered in the urine.

What are the major mechanisms for buffering secreted H⁺ in urine?

H⁺ is buffered by filtered nonvolatile buffers such as phosphate and by kidney-generated NH₃, which combines with H⁺ to form NH₄⁺.

Where is most filtered HCO₃⁻ reabsorbed?

The proximal convoluted tubule reabsorbs about 80%; the thick ascending limb reabsorbs about 10%, the DCT about 6%, and the medullary collecting duct about 4%, leaving only about 0.01% in urine.

What is the basic mechanism of renal HCO₃⁻ reabsorption?

Tubular cells secrete H⁺ into the lumen, where it combines with filtered HCO₃⁻ to form H₂CO₃. Carbonic anhydrase converts H₂CO₃ to CO₂ + H₂O; CO₂ enters the cell, HCO₃⁻ is regenerated, and HCO₃⁻ is transported into blood.

What is the function of carbonic anhydrase in HCO₃⁻ reabsorption?

It rapidly catalyzes the bidirectional interconversion of CO₂ and HCO₃⁻, allowing efficient reclamation of the large filtered HCO₃⁻ load.

Where are CA I, CA II, and CA IV located?

CA I is mainly cytoplasmic in RBCs; CA II is a ubiquitous cytoplasmic enzyme; CA IV is membrane-linked on the outer surface of the proximal tubule apical membrane.

How does HCO₃⁻ leave a proximal tubular cell for the blood?

Through the basolateral Na⁺/HCO₃⁻ cotransporter.

How is H⁺ secreted by the proximal tubule during HCO₃⁻ reabsorption?

Primarily through an apical Na⁺/H⁺ exchanger.

What drug inhibits carbonic anhydrase in this lecture?

Acetazolamide, a sulfonamide carbonic anhydrase inhibitor.

What are titratable acids?

Secreted H⁺ bound to filtered non-HCO₃⁻, non-NH₃ buffers such as HPO₄²⁻, creatinine, and urate. For example, H⁺ + HPO₄²⁻ produces H₂PO₄⁻ for urinary excretion.

How does excretion of H⁺ with phosphate generate new HCO₃⁻?

Each H⁺ secreted into the lumen and buffered by HPO₄²⁻ results in generation of a new HCO₃⁻ inside the tubular cell, which is transferred to the blood.

What determines the effectiveness of a urinary titratable buffer?

The amount of buffer in filtrate/urine, its pK, and urinary pH. An effective buffer has a pK between glomerular filtrate pH and urine pH; lower urine pH increases protonation and acid excretion.

Why is renal NH₃ different from filtered buffers?

Plasma NH₃ concentration is extremely low, so filtration contributes negligibly. The kidney generates NH₃/NH₄⁺, making it a renal-synthesized buffer system.

How does the proximal tubule generate NH₄⁺ and new HCO₃⁻?

Glutamine is metabolized to α-ketoglutarate, generating two NH₄⁺ ions; metabolism of α-ketoglutarate also generates new HCO₃⁻ that enters the blood.

How much NH₄⁺ does the proximal tubule secrete per day?

Approximately 40 mmol/day.

What transporter participates in proximal tubular NH₄⁺ secretion?

The apical Na⁺/H⁺ exchanger NHE3 participates in secretion of ammonium derived from glutamine metabolism.

What are the five major processes involved in renal NH₃/NH₄⁺ handling?

PCT secretion of NH₄⁺; tALH reabsorption of NH₄⁺ into the interstitium; recycling into the PCT/tDLH; entry of interstitial NH₄⁺/NH₃ into the collecting duct; and NH₄⁺ entry into the vasa recta and exit from the kidney.

How does the thick ascending limb reabsorb NH₄⁺?

NH₄⁺ crosses the apical membrane through the Na⁺/K⁺/2Cl⁻ cotransporter and K⁺ channels such as ROMK, producing accumulation of NH₄⁺ in the medullary interstitium.

What is ammonium recycling?

Medullary NH₄⁺ can dissociate into H⁺ and NH₃; NH₃ enters the proximal straight tubule/thin descending limb, becomes trapped as NH₄⁺, and is subsequently reabsorbed again by the thick ascending limb.

How is NH₃ handled by the medullary collecting duct?

Interstitial NH₃ enters MCD cells through RhBG/RhCG gas channels and then enters the lumen through RhCG, where it combines with secreted H⁺ to form NH₄⁺.

What is diffusion trapping of NH₃?

NH₃ diffuses into the tubular lumen and combines with secreted H⁺ to form NH₄⁺. The charged NH₄⁺ is effectively trapped in the lumen for excretion.

What are the four fundamental acid-base disturbances?

Respiratory acidosis, respiratory alkalosis, metabolic acidosis, and metabolic alkalosis.

What is the body's initial defense against an acid-base disturbance?

Intracellular and extracellular buffers immediately minimize the magnitude of the change in pH; longer-term restoration requires compensatory responses by the lungs or kidneys.

What is the primary disturbance and renal response in respiratory acidosis?

The primary disturbance is increased arterial PCO₂. The kidneys compensate by increasing H⁺ secretion and producing/reabsorbing more HCO₃⁻, including through increased NH₃/NH₄⁺ excretion.

How does acute respiratory acidosis increase renal H⁺ secretion?

In the proximal and distal tubules, increased PCO₂ promotes insertion of H⁺ pumps into apical membranes, increasing H⁺ secretion.

How does chronic respiratory acidosis affect the proximal tubule?

It upregulates apical NHE3 and basolateral NBCe1 activity, increasing H⁺ secretion and HCO₃⁻ return to the blood.

What is the primary disturbance and compensation in metabolic acidosis?

Primary HCO₃⁻ decreases and H⁺ increases, lowering pH. Pulmonary compensation is hyperventilation to lower CO₂; renal correction increases H⁺ secretion, HCO₃⁻ reabsorption/production, and NH₄⁺ excretion.

How does acute metabolic acidosis affect renal acid handling?

Low HCO₃⁻ stimulates proximal H⁺ secretion, increases H⁺ pump insertion in distal intercalated cells, and stimulates NH₃ production.

How does chronic metabolic acidosis affect citrate and calcium?

Increased proximal Na⁺-citrate uptake increases citrate metabolism and HCO₃⁻ production. Reduced plasma citrate decreases Ca²⁺-citrate excretion, increasing urinary free Ca²⁺ and risk of renal calcium stones.

What is the renal response to metabolic alkalosis?

Increased plasma HCO₃⁻ and decreased H⁺ reduce proximal H⁺ secretion, while the collecting duct shifts toward HCO₃⁻ secretion.

What is the role of β-intercalated cells in metabolic alkalosis?

β-intercalated cells have the opposite transporter orientation from α-intercalated cells and promote HCO₃⁻ secretion into the tubular lumen.

How does volume contraction affect renal H⁺ secretion?

Decreased ECF volume activates RAAS and SNS. Angiotensin II and norepinephrine stimulate proximal Na⁺/H⁺ exchange, Ang II stimulates α-intercalated cells, and aldosterone increases collecting-duct H⁺ secretion.

What principle explains why volume contraction can strongly influence acid-base handling?

Regulation of effective circulating volume takes precedence over regulation of plasma pH.

How does hypokalemia affect acid-base balance?

K⁺ depletion increases renal H⁺ secretion and promotes metabolic alkalosis. It increases proximal Na⁺/H⁺ exchange, NH₃ synthesis/NH₄⁺ excretion, and α-intercalated-cell H⁺ secretion.

How does hyperkalemia affect acid-base balance?

Hyperkalemia is often associated with metabolic acidosis because it reduces NH₄⁺ synthesis and excretion and interferes with NH₄⁺ accumulation and recycling in the renal medulla.

How does aldosterone increase H⁺ secretion?

It directly increases collecting-duct H⁺ pump activity and basolateral Cl⁻/HCO₃⁻ exchange and indirectly increases lumen-negative voltage through Na⁺ reabsorption, favoring α-intercalated-cell H⁺ secretion.

How do carbonic anhydrase inhibitors affect urine acidification?

They decrease H⁺ secretion, especially in the proximal tubule, and promote excretion of alkaline urine.

How do K⁺-sparing diuretics affect H⁺ secretion?

Amiloride and triamterene inhibit ENaC, making the collecting-duct lumen more positive and reducing H⁺ secretion; spironolactone decreases H⁺ secretion by blocking aldosterone.

Why can loop and thiazide diuretics cause metabolic alkalosis?

They cause volume contraction, increase distal Na⁺ delivery and lumen-negative voltage, and produce K⁺ wasting/hypokalemia; these effects increase renal H⁺ secretion and promote alkalosis.

What acid-base disturbance occurs at high altitude, and why can acetazolamide help?

Low PO₂ stimulates ventilation, lowering PaCO₂ and producing respiratory alkalosis with increased blood pH. Acetazolamide inhibits carbonic anhydrase, increasing urinary HCO₃⁻ loss and helping counter the alkalosis.