Renal Clearance and Its Applications

Clearance is a key concept whose definition requires emphasis. Definition of Clearance

The clearance of any substance excreted by the kidney is the volume of plasma that is cleared of the substance in unit time. Thus, the units of clearance are those of volume per unit time (usually ml/min).

Considering the clearance of a substance x, clearance is given by the formula: where:

Cx = clearance of x Ux = urine concentration of x Px = plasma concentration of x V = urine flow (ml/min).

In fact, clearance only represents a theoretical volume of plasma, since no aliquot of plasma is completely cleared of any substance during its passage through the kidney. The clearance formula has considerable usefulness for assessing renal function. Clearances of two specific substances, inulin and para-aminohippuric acid (PAH), can be used to measure GFR and the renal plasma flow respectively.

Measurement of Clearance

To determine clearance of a substance in practice, the following measurements must be made:

• Plasma concentration of the substance—must either be constant or changing in a predictable way so that an accurate average concentration can be calculated. It, therefore, follows that clearance measurements are only suitable for average or steady-state determinations of GFR and RBF and cannot be used if rapid or transient changes are occurring

• Urine concentration of the substance—urine flow must be adequate for the assay in the clearance period (which is a minimum of 10-20 min).

Inulin Clearance:

The Measurement of GFR

Inulin is a polysaccharide with a molecular weight of about 5500 Daltons. It is not a normal constituent of the body, but can be injected (or, usually, infused) intravenously to measure inulin clearance. Inulin is small enough to pass through the glomerular filter without difficulty, but is not re-absorbed, secreted, synthesized or metabolized by the kidney. Thus, all the filtered inulin is excreted and all the inulin that is excreted has entered the urine only by filtration at the glomerulus.

If urinary inulin concentration is Uin (mg/ml), and urine flow is V (ml/min), then the amount of inulin excreted per min is:

This is also the total amount of inulin that enters the nephrons contained in the filtered plasma per min. The volume of plasma containing this amount of inulin is therefore:

Pjm^nl)

where:

Pin = plasma concentration of inulin.

This volume of plasma is equivalent to the volume cleared of inulin per min i.e. the inulin clearance. Thus, the inulin clearance (Cin) is equal to GFR. The inulin clearance measurement (and, hence, GFR measurement) is independent of the plasma inulin concentration. For an adult, the normal inulin clearance (GFR) is 125 ml/min. From day to day, GFR is remarkably constant in man. Variations in excretion of water and solutes are much more dependent on changes in tubular re-absorption and secretion than on GFR changes.

If a solute has a clearance value higher than the inulin clearance, then the solute must get into the renal tubules not only by glomerular filtration, but also by tubular secretion (PAH is such a substance, see below). However, if a solute has a clearance value less than that of inulin, there are two possibilities:

• The solute may not be freely filtered at the glomerulus

• The solute is freely filtered but is then re-absorbed from the tubule Creatinine Clearance

Because measurements of inulin clearance involve exogenous inulin administration it is rarely used clinically. An alternative way to measure GFR is by using creatinine clearance. Creatinine is a product of muscle metabolism, and as long as the subject remains at rest, the plasma creatinine level stays reasonably constant. Like inulin, it is freely filtered and not reabsorbed, synthesized or metabolized by the kidney, but creatinine is secreted to some extent by the tubules. This tends to make the value for creatinine clearance higher than that for inulin clearance, since the term (U.V) in the formula for clearance is artifactually high. However, as the plasma creatinine assay is not absolutely specific and overestimates the true plasma creatinine concentration, the two errors tend to cancel each other out, and creatinine clearance becomes a reasonable estimate of GFR.

PAH Clearance:

Measurement of Renal Plasma Flow

PAH is one of the groups of organic acids secreted by the proximal tubule. PAH is not only secreted, but also is filtered at the glomerulus. Thus, the total amount of PAH excreted is equal to the sum of the amount filtered plus the amount secreted. PAH is almost completely removed from the plasma by the kidneys, even though only a fraction of the plasma is filtered. The clearance of PAH, therefore, provides a measurement of the total renal plasma flow (RPF). (It should be noted that this relationship only holds as long as the tubular maximum, Tm, for the transport of PAH is not exceeded. Tm is reached at a plasma concentration of about 10 mg/100ml plasma.)

At plasma concentrations < 10 mg/100 ml:

PAH delivered to kidneys in plasma = PAH excreted in urine. The amount of PAH excreted in the urine is given by: (urinary concentration of PAH) x (urine flow), which can be expressed as

where:

UPAH = urinary concentration of PAH V = urine flow (ml/min).

Also, the PAH delivered to the kidneys is given by: (renal plasma flow) x (plasma concentration of PAH) which can be expressed as where:

PPAH = plasma concentration of PAH RPF = renal plasma flow. Therefore, it follows that

As can be seen, this is also the clearance formula for PAH. A typical value for RPF is 600 ml/min. Calculation of Renal Blood Flow

Given the haematocrit, renal blood flow (RBF) can be obtained. A typical haematocrit is 45%, which means that 45% of the total blood volume is cells and, therefore, 55% is plasma. So renal blood flow can be calculated by:

which gives about 1091 ml/min.

The clearance of PAH, although generally used as a measure of renal plasma flow, does not measure the plasma flow exactly, because PAH is not completely cleared from the blood during one passage through the kidney. The PAH extraction is only about 90% complete, due to that not all of the blood which enters the kidney goes to the glomeruli and tubules. Some goes to the capsule, the perirenal fat and the medulla (the blood in the vasa recta has had some PAH removed by filtration, but is not available for secretion). PAH clearance approximates to cortical plasma flow and is usually called the effective renal plasma flow.

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