Tubular secretion of PAH

Definitions & Key takeaways

Para-aminohippuric acid (PAH) is a substance that is freely filtered by the glomeruli in the kidneys and secreted by the tubular cells into the tubular fluid. The secretion of PAH occurs primarily in the proximal tubule of the nephron and is facilitated by transporters located on the luminal surface of the tubular cells.

The amount of PAH that is secreted by the kidneys is used to estimate the renal blood flow, which is an important parameter in the assessment of kidney function. Since nearly all of the PAH that is filtered by the glomeruli is secreted by the tubular cells, the amount of PAH that is excreted in the urine is directly proportional to the amount of blood that is flowing through the kidneys.

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Introduction0:00–1:51

If we take a cross-section of the kidney, there are two main parts, the outer cortex and the inner medulla. If we zoom in, there are millions of tiny functional units called nephrons which go from the outer cortex down into the medulla and back out into the cortex again.
These nephrons perform the major function of the kidney, which is to clear harmful substances from the body by filtering the blood.
Each nephron is made up of the glomerulus, or a tiny clump of capillaries, where blood filtration begins. Interestingly, once the blood leaves these glomeruli it does not enter into venules.
Instead the glomerulus funnels blood into efferent arterioles which divide into capillaries a second time. These peritubular capillaries then reunite and at that point the blood enters venules and eventually drains back into the venous system.
Now, when blood gets filtered, some fluid remains in the glomerulus, and some fluid goes into the renal tubule. The renal tubule is a structure with several segments: the proximal convoluted tubule, the U- shaped loop of Henle with a descending and ascending limb and the distal convoluted tubule, which winds and twists back up again, before emptying into the collecting duct, which collects the final urine.
Now, zooming in on this nephron’s tubule, each one’si lined by brush border cells which have two surfaces. One is the apical surface which faces the tubular lumen and is lined with microvilli, which are tiny little projections that increase the cell’s surface area to help with solute reabsorption.
The other is the basolateral surface, which faces the peritubular capillaries, which run alongside the nephron. Alright, now, one substance that’s filtered out of the glomerulus and into the tubule is para-aminohippuric acid, or PAH for short.

Para-aminohippuric Acid (PAH)1:51–2:40

Actually, PAH is an organic acid, and about 90% is bound to plasma proteins. So, really, only the unbound 10% can pass through the glomerular capillaries.
Essentially, the higher the unbound PAH concentration, the more PAH will get filtered. If we wanted to illustrate this in a graph, with the unbound PAH concentration in the blood on the x axis and the PAH filtered on the y axis, we would see that as the unbound concentration of PAH increases, the filtered load of it is also going to increase in a linear fashion.

Reabsorption and Secretion2:40–3:15

Now, in the renal tubule, reabsorption, is when something moves from the renal tubular back into the blood, and actually no PAH is reabsorbed.
Secretion on the other hand, is when something from the blood moves into the renal tubule. And in fact, an additional bit of PAH is secreted from the peritubular capillary blood into tubular fluid.
To accomplish this, the basolateral membrane of the tubular cells has a special type of carrier protein that transports PAH, as well as other organic anions.
So, now let’s add the PAH secreted to the graph, also on the y axis. At first, the higher the PAH concentration in the blood, the more PAH will get secreted into the tubule.

Transport Maximum3:15–3:52

But there’s only a limited number of carrier proteins available on those tubular cells, which means that at some point they’re working at full capacity and no additional PAH will allow them to work any faster.
This is known as the Tm or transport maximum. After this point, the secretion of PAH stays constant even with increasing PAH concentration.

Excretion3:52–4:35

Finally, we can add PAH excreted in the urine to the graph, and excretion in the urine is the sum of the filtered PAH plus the secreted PAH.
In our graph, below Tm, small increases in plasma PAH concentration give rise to steep increases in PAH excretion, since both filtration and secretion are rising along.
Above Tm, though, secretion gets saturated, so with increases in plasma PAH concentration only the filtration component increases, and excretion rises less sharply and becomes parallel to the filtration curve.

Fick Principle4:35–5:38

Okay, now, the reason PAH matters is that it can be used to estimate the blood plasma reaching the kidneys per unit time.
Just like any other substance reaching the kidneys, the amount of PAH entering the kidney has to equal the amount of PAH leaving the kidney - that’s the Fick’s principle.
PAH enters the kidney through the renal artery, and there are two ways a substance could leave the kidney: either by leaving through the renal vein or by going into the urine.
What’s unique about PAH is that at low PAH concentrations, below Tm, some PAH gets filtered in the glomerulus and the remainder of PAH that bypasses the glomerulus, gets secreted from the peritubular capillaries into the tubules.
So in the end, all blood plasma leaving the kidneys is free from PAH. In other words, the amount of PAH in the renal vein is practically zero, and the amount of PAH entering the kidney via the renal artery equals the amount of PAH excreted in the urine.

Renal Plasma Flow Equation5:38–7:04

Now, the amount of PAH entering the kidney is equal to the concentration of PAH in the renal artery times renal plasma flow, or RPF for short, which is the volume of plasma, often liters, delivered to the kidneys each minute.
Likewise, the amount of PAH excreted in the urine is equal to the concentration of PAH in the urine U times the urine flow rate, which is the volume of urine formed per minute.
Remember, since the amounts are the same, that means these two equations are equal. We can solve for renal plasma flow by dividing by the concentration of PAH in the renal artery.
So we have the concentration of PAH in the urine U, which is milligrams of PAH per milliliter of urine (mg/ml) times urine flow rate V, or milliliters of urine formed per minute (ml/min) all divided by the concentration of PAH in the renal artery, which is milligrams of PAH in each milliliter of plasma (mg/ml).
And when it’s all said and done you end up with renal plasma flow, in ml of plasma per minute. This makes it fairly easy to calculate renal plasma flow.
That’s not always 100% accurate, though, since it’s possible that a tiny amount of PAH has remained in the renal vein, so the estimated renal plasma flow is usually thought to be within 10% of the true renal plasma flow.

Renal Blood Flow Equation7:04–8:15

Now, to convert the renal plasma flow to renal blood flow, we must also take into account the volume of blood occupied by red blood cells.
A hematocrit of 40%, for example, means that red blood cells occupy 40% of the blood volume and plasma accounts for the remaining 60%.
The total renal blood flow is measured by dividing the clearance of PAH by the fractional blood volume occupied by plasma, which is 1 minus the hematocrit.
Normally, because all of the PAH gets cleared by the kidney, renal plasma flow equals PAH clearance. However, at very high PAH concentrations, above Tm, PAH continues to get freely filtered, but the PAH that bypasses the glomerulus, starts to overwhelm the carrier proteins in the tubule.
As a result, secretion will reach its saturation point and some of this PAH will be left behind in the plasma and PAH in the renal artery will no longer be equal to the PAH in the urine!
In fact, this means PAH in the urine starts to fall below the PAH in the renal artery. All right, as a quick recap, below the transport maximum, all the para-aminohippuric acid, or PAH, making it to the kidneys is removed from blood that passes through the kidneys, and above the transport maximum the carrier proteins in the nephron are saturated and some PAH gets left in the blood.

Review8:15–8:47

In the former case, the renal plasma flow can be estimated by taking the concentration of PAH in the urine times urine flow rate V, all divided by the concentration of PAH in the renal artery.