OBJECTIVE 2: TO UNDERSTAND THE CONCEPT OF CLEARANCE.

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A. Clearance is a term used to describe the rate at which the blood is cleared of a substance. It is often used to measure the efficiency of the kidney in removing a substance from the blood. As an example (fig. 4-1): To excrete a substance such as inulin, the kidney filters a large volume of plasma containing inulin, then the tubular cells reabsorb almost all of this fluid, returning it to the circulation without inulin, which remains behind and is excreted in the urine. By this process, the kidney has "cleared" a volume of plasma of the inulin contained within it. Thus the volume of plasma cleared of inulin per unit time (C_in) equals the rate of inulin excretion divided by the concentration of inulin in the plasma from which it was removed:

C_in = U_inV / P_in   (ml/min)    Eq. 9

For inulin the clearance rate is equivalent to the GFR. For PAH the clearance rate is equivalent to the RPF. The clearance volume is a virtual volume, the smallest volume of plasma sufficient to account for the amount of the substance excreted per unit time.

1. For reabsorbed substances, the apparent volume of plasma cleared of the substance/time is smaller than the filtered volume since some of the substance is returned to the plasma from the filtrate by the tubular cells (Fig. 4-2). Nevertheless, the amount excreted/time (U_sV) can be considered to have been contained in a virtual volume of plasma (C_s) at the plasma concentration:

C_s = U_sV/P_s (ml/min)

The volume of plasma from which that substance is removed is less than the GFR or C_in.

2. For substances that are filtered and secreted but not reabsorbed to a significant extent, the amount excreted/time exceeds the amount filtered/time. The volume of plasma cleared of the substance/time is larger than the GFR or C_in because the tubular cells are also removing the substance from plasma in the peritubular capillaries (Fig. 4-3). Still, the amount of the substance excreted/time was contained initially in a certain volume of plasma at the plasma concentration. The standard clearance equation given above may be used to calculate the apparent volume of plasma that was cleared by both filtration and secretion.

B. To summarize, clearance may be defined as the virtual volume of the plasma from which the kidney has removed or 'cleared' a substance per unit time or, to state it another way, clearance is the virtual volume of plasma that contained the mass of a substance that the kidney excreted in a unit of time. For a substance that is neither reabsorbed nor secreted and meets the other criteria given, the clearance rate equals the GFR. From here on the terms GFR and C_in will be used interchangeably. For a substance that is filtered and reabsorbed, C_s<C_in and for a substance that is filtered and secreted, C_s>C_in. These facts are used experimentally to determine how substances are handled by the kidney.

1. For substances that are filtered only, the rate that it is filtered and excreted will increase as the plasma concentration rises, but the volume of fluid that is filtered will not change; thus the volume of fluid that is cleared will not change (A in Fig. 4-4).

Fig. 4-4. Effect of plasma concentration of a substance on its clearance. A. Substance that is filtered only. B. Substance that is reabsorbed. C. Substance that is secreted.

2. The transport processes for substances that are reabsorbed and secreted usually can handle only limited amounts and this affects the clearance rates.

As the plasma concentration of a reabsorbed substance rises and the amount filtered increases, the transport process becomes saturated and a greater fraction of the filtered amount escapes reabsorption and is excreted. Because of this, a larger fraction of the filtered fluid is returned to the circulation cleared of the substance, in other words the clearance rate increases (B in Fig. 4-4).

As the plasma concentration of a secreted substance increases and the transport process becomes saturated, a smaller fraction of the total amount in the blood, flowing past the tubular cells, is secreted into the tubules and the volume of plasma cleared of the substance by this process falls (C in Fig. 4-4).

Fig. 4-5. The effect of changes in P_g on its rates of filtration, reabsorption, excretion and clearance.

3. An example of the changes that occur when the plasma concentration of a reabsorbed substance such as glucose is increased is illustrated in Fig. 4-5. At the normal plasma level (80 to 100 mg/dl), all filtered glucose is reabsorbed (Fig. 4-5A) and C_g = 0 (Fig. 4-5B). As the plasma concentration rises (100 to 200 mg/dl), the amount filtered/min, and thus the amount presented for reabsorption, increases. The rate of reabsorption increases initially, no glucose is excreted and C_g still equals zero. If the plasma concentration continues to increase (>300 mg/dl), the maximum transport rate (Tm_g) is reached. As the amount filtered/min continues to rise above that point, there is no further increase in reabsorption, the excess is excreted at an increasing rate, and the volume of plasma cleared of glucose/min increases and approaches the volume filtered.

QUESTIONS: 
4. Why does the clearance of glucose change as the plasma concentration rises? What other substances would follow a similar pattern? Why does the clearance of PAH change as the plasma concentration rises? What other substances would follow a similar pattern?

5. Fundamentally, what does the clearance equation measure? Why is it that one can use the same clearance equation to calculate RPF (C_pah) and GFR (C_in)?

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