Renal Acid Base Regulation

Regulation of hydrogen ions (H⁺)

Most of the acid in the body is buffered by the carbon dioxide/bicarbonate (CO₂/HC0₃^-) system:

The partial pressure of CO₂ (PaCO₂) is regulated by the lungs and changes in alveolar ventilation, whereas the plasma concentration of HC0₃^- is regulated by the kidneys. Indeed, the pH of blood is simply a constant plus the ratio of HC0₃^- to PaCO₂. More simply, we can think of pH varying in proportion to this ratio, or more simply what the kidneys are doing relative to the lungs.

What matters is the ratio, not the absolute values of HC0₃^- and PaCO₂. The body may compensate for a disturbance in one with an alteration in the other. So, you may encounter a patient with very odd HC0₃^-, but an equally odd PaCO₂ and a relatively normal pH. What is going on here is compensation – there is an unresolved acid-base irregularity but the body is managing to compensate.

A simple model

When we are thinking about the overall role of the kidney in acid-base regulation, we can simplify the work of all the component parts into a simple model that ignores the complex anatomy and different functional components of this organ. Such a model is not helpful in understanding diseases of the kidney, but is satisfactory for our needs here. The way the kidney regulates H+ ions is by regulating whether HC0₃^- is added to blood or allowed to be excreted into the urine. So:

1. In acidaemia, urine is acid, not because H⁺ has been secreted into the urine, but because filtered HC0₃^- has been removed.
2. In alkalaemia, urine is basic, because filtered HC0₃^- has been allowed to stay in the urine, not because H⁺ has been removed.

Neither of these is truly an active response to the change in pH of blood, but rather what happens to the existing mechanics of the regulation of HC0₃^- when the concentration of plasma H⁺ ions changes. In either case though, the change in HC0₃^- regulation helps compensate for the acid-base disturbance. The way the kidneys actively regulate HC0₃^- is by altering metabolism of glutamine, which is broken down into NH4+ and HC0₃^-; this new HC0₃^- is pumped back into the blood. The enzyme responsible for glutamine metabolism (glutaminase) is induced by chronic acidosis, which provides additional renal compensation in this acid-base disturbance.

The three processes (although the first two are quite similar) by which the kidney regulates plasma HC0₃^- are summarised in Figure 1 (below). Remember, this is an oversimplification of total renal function and does not consider the many different mechanisms by which ions may enter or leave cells, nor which parts of the kidney these mechanisms occur in.

Figure 1: Summary of the three main ways that the kidney can regulate plasma bicarbonate, and hence plasma [H⁺]. Important note: these three mechanisms occur in various parts of the kidney and this figure serves as a simple overview of total kidney function only. (A). Carbonic anhydrase (CA) catalyses the formation of H⁺ and HC0₃^- from water and CO₂. HC0₃^- is transported into the blood and H⁺ is transported into the urine where it is partially buffered by filtered HC0₃^-. Note, the mechanisms for transporting H⁺ out of the cell are manifold and depend on the specific region of this kidney under consideration. (B). New HC0₃^- is also produced if the supply of filtered HC0₃^- is exhausted in the tubules by complete reabsorption. HC0₃^- and H⁺ are produced in the same was as in panel (A), it’s just that the transported H⁺ is combined with filtered HPO₄^2- and excreted. (C). Finally, tubular epithelial cells metabolise glutamine into NH₄⁺ and HC0₃^-. This reaction is catalysed by the enzyme glutaminase, the levels of which are regulated according to acid-base balance. Glutaminase is induced by chronic acidosis to assist in HC0₃^- production (mainly in the proximal tubule). (Redrawn with minor adaptation from Vander’s Physiology).

Renal response to acidosis

If there is an increased concentration of H⁺ in plasma, then sufficient H⁺ will be secreted into the tubules (Panel A) to allow complete reabsorption of all of the filtered HC0₃^-, increasing plasma HC0₃^-. Any additional H⁺ will be excreted bound to non-bicarbonate buffers such as HPO₄^2- (Panel B). Finally, if acidosis persists, glutaminase expression will be induced to produce further HC0₃^- (and NH₄⁺; Panel C). The result will be increase acidification of the urine and increased plasma HC0₃^- to buffer H⁺.

Renal response to alkalosis

If there is a decreased concentration of H⁺ in plasma, then insufficient H⁺ will be secreted into the tubules and excess HCO₃^- and other buffers will be left in urine, meaning less is reabsorbed into plasma (Panels A & B). Glutaminase is not induced, so further HC0₃^- production is reduced (Panel C). Overall, plasma HC0₃^- levels are reduced and the urine is allowed to become alkaline.