Urinary Regulation of Acid-Base Balance

Overview of Mechanisms

The kidneys regulate blood pH through 2 mechanisms:

• The excretion of hydrogen ions (H⁺) as dihydrogen phosphate (H₂PO₄⁻) or ammonium ions (NH₄⁺)
• The reabsorption, production and secretion of bicarbonate ions (HCO₃^–) .

Excretion of Hydrogen Ions

As Dihydrogen Phosphate

Phosphate is freely filtered at the glomerulus entering the tubular lumen. 85% of this is normally reabsorbed while the rest remains in the filtrate, maintaining a relatively high phosphate concentration in the tubular fluid. Simultaneously, in the distal nephron, H⁺ ions are actively transported into the lumen via hydrogen-ATPase pumps on alpha-intercalated cells.

Excess luminal phosphate binds to secreted H⁺ ions in the distal nephron to form dihydrogen phosphate (H₂PO₄⁻), which is then excreted in urine. By buffering hydrogen ions in this way, phosphate prevents the accumulation of free H⁺ ions in the tubular fluid and limits the generation of a H⁺ ion concentration gradient.

This enables continual active secretion of hydrogen ions whilst maintaining tubular pH and preventing their reabsorption back into the tubular epithelial cells. This excretion of H⁺ ions increases blood pH.

As Ammonium

In the epithelial cells of the proximal convoluted tubule (PCT), glutamine undergoes ammoniagenesis, where it is metabolised into glutamate and ammonium (NH₄⁺). This ammonium ion is transported into the lumen via the sodium–hydrogen (Na⁺/H⁺) exchanger in place of the hydrogen ion.

Luminal ammonium dissociates into ammonia (NH₃) and H⁺ ions. Ammonia, being small and uncharged, can freely diffuse across the cell membrane to the interstitium and from there to other parts of the nephron, whilst H⁺ ions can be used to reabsorb bicarbonate in a process described later.

Since the pH of the proximal tubule is more alkaline, the equilibrium of ammonia and ammonium ions tends to favour the freely diffusible ammonia. When this ammonia diffuses into the more acidic distal tubule it tends to re-combine with the luminal H⁺ ions secreted by alpha-intercalated cells in order to buffer this acid.

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Figure 1
Ammonia/Ammonium buffer system in renal acid-base regulation

The ammonium ions (NH₄⁺) re-formed in the distal tubule become trapped here and are excreted in urine. This mechanism allows H⁺ ions to be removed from the body, increasing blood pH.

Note: The glutamate produced by ammoniagenesis can go on to form 2 bicarbonate ions (via its conversion to alpha-ketoglutarate) which can then be reabsorbed, further increasing blood pH.

Regulation of Bicarbonate Ions

Bicarbonate ions are a major buffer in the blood. The kidneys play a crucial role in maintaining the pool of bicarbonate ions, preserving its buffering capacity even as it is being used up. It does this by reabsorbing all bicarbonate that is freely filtered in the glomerulus and producing new bicarbonate ions to replace those used up in buffering acids.

Reabsorption

85% of bicarbonate reabsorption occurs in the PCT. However, tubular epithelial cells are largely impermeable to bicarbonate, meaning that bicarbonate cannot be reabsorbed directly from the lumen. Instead, reabsorption occurs through a secondary active cyclical mechanism involving the secretion of H⁺ ions.

In the proximal tubule, H⁺ ions are secreted into the lumen via the sodium–hydrogen (Na⁺/H⁺) exchanger. These ions combine with filtered intraluminal bicarbonate to form carbonic acid (H_₂CO₃). Luminal carbonic acid is then converted to carbon dioxide (CO₂) and water (H₂O), catalysed by carbonic anhydrase (an enzyme present on the luminal surface of the PCT).

Luminal carbon dioxide diffuses across the membrane back into tubular epithelial cells. Here, the reaction is undone and carbon dioxide re-combines with intracellular water to reform carbonic acid, catalysed by carbonic anhydrase within the cell. This intracellular carbonic acid dissociates into H⁺ and HCO3⁻ ions.

The intracellular bicarbonate ions are transported across the basolateral membrane into the bloodstream via the sodium–bicarbonate (Na⁺/HCO₃⁻) symporter. The intracellular H⁺ ions are transported back into the tubular lumen through the Na⁺/H⁺ exchanger, allowing the cycle to repeat and more luminal bicarbonate to be reabsorbed into the bloodstream.

By OpenStax College [CC BY 3.0 (http://creativecommons.org/licenses/by/3.0)], via Wikimedia Commons

Figure 2
Diagram showing reabsorption of bicarbonate within the kidney.

Production

The kidney is also able to produce bicarbonate. The high metabolic activity of renal cells produces large amounts of carbon dioxide, which reacts with water to form carbonic acid. This dissociates to produce HCO₃^–  and H⁺ ions. The bicarbonate ions are absorbed into the bloodstream, while the hydrogen ions are secreted into the tubular lumen.

This is useful as it also provides H⁺ ions to drive HCO₃^– reabsorption.

In addition to this, bicarbonate ions can be produced from amino acids (mainly glutamine) via ammoniagenesis, producing glutamate and ammonium ions. The ammonium ion is excreted in the urine as described above. However, the glutamate is converted into alpha-ketoglutarate which is used to create 2 bicarbonate ions.

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Figure 3
Renal regulation of acid–base balance via proximal tubule ammoniagenesis and distal nephron acid secretion. Please note diagram is illustrative. Luminal walls are not anatomically apposed

Secretion

Although the majority of filtered bicarbonate is reabsorbed along the nephron, bicarbonate can also be secreted in the collecting ducts by β-intercalated cells, providing a mechanism for renal compensation during alkalosis.

Clinical Relevance

Anion Gap

The anion gap is a way of determining the cause of metabolic acidosis. The idea behind it is that to maintain a net neutral charge in the body, the number of positive ions (cations) and negative ions (anions) should balance out. This is calculated by using the anion gap formula:

By TeachMeSeries Ltd (2026)

Figure 4
Formula for calculating the anion gap

A normal anion gap is usually 8-12mEq/L. This is because there are naturally slightly more cations than anions. If the anions featured in the calculation (Cl^– and HCO₃^–) increase then the cations in the equation also increase to compensate for this and the anion gap remains normal.

However, if the amount of organic anion (e.g. lactate) increases then they will take up more of the anions contributing to the neutral charge in the body. This means that there will be fewer of the Cl^– and HCO₃^– anions that contribute to the formula, so the calculated anion gap will increase.

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Figure 5
(A) Normal anion gap (B) Increased anion gap metabolic acidosis. Figure does not include other ions not included in the calculation