76. Compensation of pH-abnormalities (plasma and intracellular puffers, respiration, kidney) and their disturbances

Page created on December 17, 2018. Last updated on May 27, 2019 at 16:16

Basics

In arterial plasma is the concentration of H⁺ around 4 x 10^-8 moles per litre. pH = -log([H⁺]), so the plasma pH is around -log(4 x 10^-18) = 7.4 approximately. Indeed is the normal range of pH in the blood between 7.35 and 7.45, although pH down to 6.8 and up to 7.8 is survivable.

The intracellular pH in the cytoplasm is around 7.2, but the pH in other organelles differ. An important thing to remember about pH balance is that the goal isn’t to keep the pH of the plasma within normal range but rather to keep the pH of the cells normal. It turns out however that, because all fluid compartments of the body are interconnected, does a normal plasma pH mean a normal cell pH in most cases.

Bicarbonate = [HCO₃^–]

Carbonic acid = [H₂CO₃]

Buffers

The body uses acid-base buffers to keep the pH within normal levels. The body has multiple buffers:

• Carbonic acid / bicarbonate buffer – HCO₃^– / H₂CO₃
• Phosphate buffer – HPO₄^2- / H₂PO₄^–
• Plasma proteins
• Haemoglobin
• Intracellular buffers

The carbonic acid buffer is by far the most important, however also a bit complicated, because it exists in an equilibrium, like this:

In plasma is the level of H₂CO₃ very low. Any H₂CO₃ is either dissolved into HCO₃^– or split into H₂O and CO₂ by carbonic anhydrase. The equation can therefore be simplified to look like this:

You probably remember the Henderson-Hasselbalch equation. It looks like this:

Let’s plot in the pK for H₂CO₃, which is 6.1. Let’s also add the base (HCO₃^–) and the acid. However, since H₂CO₃ is converted into CO₂ by carbonic anhydrase will we write CO₂ as our acid instead of H₂CO₃.

But CO₂ is a gas, not a solute. The only way to measure the level of CO₂ in the blood is by partial pressure. To input the partial pressure into this equation we need to convert partial pressure into a unit of concentration. The explanation isn’t important, but to use CO₂ in this equation we must multiply the pCO₂ by 0.03. The equation now looks like this:

The normal value of [HCO₃^–] is 24 mM, while the normal pCO₂ is 40. 40 x 0.03 = 1.2, so we’ll input that.

So when [HCO₃^–] and pCO₂ are both normal is the pH 7.4. You should remember that 24:1.2 = 20:1

Another important thing to notice here is that the level of pCO₂ and [HCO₃^–] isn’t directly responsible for the pH, but rather the ratio between the two, 20:1. In fact, in many pathological cases will one of these parameters increase or decrease, which ruins the 20:1 ratio. The body will compensate for this by increasing or decreasing the other parameter accordingly, to try to maintain the 20:1 ratio and therefore the normal pH.

Let’s take an example. You start hyperventilating. This decreases the pCO₂, which makes the [HCO₃^–]:[pCO₂] ratio higher than 20:1. This means that the pH increases. What can the body do to compensate? The kidney will excrete more HCO₃^–. This returns the ratio toward the normal 20:1, which causes the pH to get closer to normal.

This buffer is a very good one, as the body can regulate both pCO₂ and [HCO₃^–] by two separate mechanisms, respiration and excretion respectively. There are also large amounts of both in the blood, so the buffer has a large buffer capacity.

The other buffers aren’t as important. They mostly work when the carbonic acid level is acutely increased or decreased. The bones however are actually important parts of the buffer, as they store a lot of phosphate, which comprises the phosphate buffer.

The plasma buffers works almost immediately after the pH change. The intracellular buffer however may take 6 – 8 hours to kick in.

Important terms

There are some important terms in connection with this we should know.

There are two ways to express the level of bicarbonate in the blood. We can express the actual bicarbonate, which is the actual number of bicarbonate molecule in the blood. The other way is standard bicarbonate, which what the number of bicarbonate molecules would have been if the pCO₂ level was normal.

Standard bicarbonate is measured by putting the serum sample in a machine that changes the pCO₂ level of the sample to 40 mmHg. It then measures the bicarbonate concentration. This is therefore a measurement that is “standardized” to 40 mmHg pCO₂, hence standard bicarbonate.

It’s important to distinguish the two because bicarbonate and pCO₂ depend highly on each other, as they’re in an equilibrium. If you slow down your breathing will pCO₂ increase. Because CO₂ and bicarbonate are in an equilibrium will some of the extra CO₂ molecules be converted into bicarbonate so that the actual bicarbonate increases. However, nothing has actually happened that increases bicarbonate by itself – it was just raised because pCO₂ was. We need a method to measure what the bicarbonate would be if the pCO₂ level is normal. This is where the standard bicarbonate comes in. The standard bicarbonate in this case would be unchanged.

Standard bicarbonate allows us to measure whether the bicarbonate increase (or decrease) is due to a primary change in pCO₂ (a respiratory condition. Standard bicarbonate would be unchanged) or due to a primary change in bicarbonate (a metabolic condition. Standard bicarbonate would be abnormal).

An example where standard bicarbonate would increase would be if there was a reduction in bicarbonate excretion in the kidneys for example.

Buffer base (BB) is a measurement of the total amount of buffer in the plasma. It’s the sum of standard bicarbonate, haemoglobin and other buffers in the blood, and the normal value is 46 mmol/L.

The base excess (BE) measures how much the buffer base has deviated from the normal value of 46 – 48 mmol/L. For example, if the buffer base is 45 mmol/L would the base excess be -1. If the buffer base is 48 would the base excess be 2.

Two organs are essential in pH homeostasis: the lungs and the kidneys.

Regulation of pH by the lungs

The lungs are important in the regulation. At rest is 20 000 mmol CO₂ eliminated by respiration daily. To give you an example of how important the lungs are: If respiration was stopped for 20 minutes would pH fall below 7.0.

Increased metabolism, such as during exercise, produces a lot of CO₂. However, healthy lungs can easily excrete more CO₂ than the metabolism can produce. By increasing respiratory frequency and depth can the lungs increase the CO₂ elimination to accommodate the increased CO₂ production.

The lungs are good at compensating for metabolic acidosis, as they can simply increase the ventilation. However, they’re not as good at compensating for metabolic alkalosis. In theory can they decrease ventilation to withhold more CO₂, but that decreases pO₂ as well. When the pO₂ level reaches 60 mmHg would the hypoxaemia start to increase the respiratory drive, limiting further compensation.

Ventilatory compensation can start relatively quickly after the pH change. It reaches maximum capacity around 24 hours after the change. Renal compensation starts later, as we will see.

Regulation of pH by the kidneys

The kidneys don’t excrete as much acid as the lungs, just more than 35 mmol H⁺ equivalent daily, potentially up to 100 mmol if needed. The kidneys can normally make the urine pH as low as 4.4, but not lower.

The kidney has three mechanisms to regulate pH. The net result of them is that H⁺ is excreted and that sodium bicarbonate is reabsorbed.

You should know that the details of the three mechanisms aren’t really important. You shouldn’t learn the drawings and ion transports by heart, but you should know what goes on in each mechanism and which RTA corresponds to which mechanism.

Mechanism 1 occurs in the proximal tubular cells and mostly does bicarbonate reabsorption. It works like this:

1. The tubular cell uses carbonic anhydrase to convert intracellular CO₂ + H₂O -> HCO₃^– + H⁺
2. H⁺ is excreted into the tubular lumen in exchange for Na⁺
3. Intracellular HCO₃^– and Na⁺ is absorbed through the basolateral membrane into the capillaries (This step doesn’t work in RTA II)
4. Inside the filtrate is H⁺ combined with HCO₃^– to form CO₂ and H₂O
5. CO₂ is a gas and therefore diffuses back into the tubular cell and further into the capillaries
6. CO₂ is eliminated by respiration

Substance	Molecules after step 2	Molecules after step 5
Na+	1 in the filtrate	1 in the blood
HCO3–	1 in the filtrate, 1 in the cell	1 in the blood
CO2	0	1 in the blood (converted from HCO3–)
H+	1	0
H2O	0	1 in the filtrate

The net result is that 1 HCO₃^– and 1 Na⁺ has been absorbed from the filtrate into the blood.

Mechanism 1. Bicarbonate reabsorption in proximal tubule

Mechanism 2 occurs in the distal tubules and mostly excretes H⁺. It works like this:

1. The cell uses carbonic anhydrase to produce HCO₃^– and H⁺ from CO₂
2. The cell excretes H⁺ by active transport (This step doesn’t work in RTA I)
3. The cell absorbed Na⁺ to maintain electroneutrality
4. Intracellular Na⁺ and HCO₃^– is absorbed into the capillaries

Substance	Molecules after step 2	Molecules after step 4
Na+	1 in the filtrate	1 in the blood
HCO3–	1 in the cell	1 in the blood
CO2	0	0
H+	1 in the cell	1 in the filtrate

The net result is that 1 CO₂ has been converted into HCO₃^– and H⁺. The former has entered the blood while the latter is excreted in filtrate. Na⁺ is also reabsorbed from the filtrate.

Note that the HCO₃^– wasn’t reabsorbed from the filtrate – it was generated inside the cell. This helps to improve the plasma bicarbonate level.

Mechanism 2. Proton excretion in the distal tubule

Mechanism 3 also occurs in the distal tubules and excretes ammonia that binds to H⁺ in the filtrate to make the filtrate less acidic, to prevent it from damaging the tubules.

1. NH₃ is produced from glutamine inside tubular cells
2. NH₃ is excreted into the filtrate
3. NH₃ combines with H⁺ in the filtrate to form NH₄⁺

The result is that there are fewer H⁺ in the filtrate, so it’s not as acidic. As a bonus did the kidney get rid of some toxic NH₃ too!

The net result of all three mechanisms is that H⁺ is excreted and sodium and bicarbonate is reabsorbed. These processes are activated by high pCO₂ (respiratory acidosis), or a decrease in bicarbonate (metabolic acidosis). They’re inhibited by alkalosis.

This kidney compensation is a slow process. It needs 24 hours to start, and 72 hours to reach maximal capacity.