Inulin is an exogenous starch-like fructose polymer that is extracted from the Jerusalem
artichoke and has a molecular weight of 5000.
Inulin is freely filtered at the glomerulus, but neither reabsorbed nor secreted by the
renal tubules (Figure 33-1A). Additional requirements for a glomerular marker, which
inulin also fulfills, are that the substance is not metabolized or synthesized by the
kidney, is non-toxic, and has no effects on GFR.
Figure 33-1A
Assuming that GFR does not change, three tests prove that inulin clearance is an
accurate marker of GFR.
First, shown in Figure 33-1B, the rate of inulin excretion (UinV) is directly proportional
to the plasma inulin concentration (Pin), as implied by Equation 33-1. The slope in
Figure 33-1B is the inulin clearance.
Second, inulin clearance is independent of the plasma inulin concentration (Figure 331C). This conclusion is already implicit in Figure 33-1B, where the slope (i.e., inulin
clearance) does not vary with Pin.
Equation 33-1
Figure 33-1B
Figure 33-1C
Third, inulin clearance is independent of urine flow. Given a particular Pin, after the
renal corpuscles filter the inulin, the total amount of inulin in the urine does not change.
Thus, diluting this glomerular marker in a large amount of urine or concentrating it in a
small volume, does not affect the total amount of inulin excreted (UinV). If the urine
flow is high, the urine inulin concentration will be proportionally low, and viceversa.
Because (UinV) is fixed, (UinV)/Pin is also fixed.
Two lines of evidence provide direct proof that inulin clearance represents GFR. First,
by collecting filtrate from single glomeruli, Richards and coworkers showed in 1941
that the concentration of inulin in Bowman’s space of the mammalian kidney is the
same as in plasma. Thus, inulin is freely filtered. Second, by perfusing single tubules
with known amounts of labeled inulin, Marsh and Frasier showed that the renal tubules
neither secrete nor reabsorb inulin. Although the inulin clearance is the most reliable
method for measuring GFR, it is not practical for clinical use. One must administer
inulin intravenously to achieve reasonably constant plasma inulin levels. Another
deterrent is that the chemical analysis for determining inulin levels in plasma and urine
is sufficiently demanding to render inulin unsuitable for routine use in a clinical
laboratory. The normal value for GFR in a 70 kg adult male is approximately 125
ml/min. Population studies show that GFR is proportional to body surface area. Because
the surface area of an average 70 kg male is 1.73 m2, the normal GFR in males is often
reported as 125 ml/min per 1.73 m2 of body surface area. In females, this figure is 110
ml/min per 1.73 m2. Age is a second variable. GFR is very low in the newborn, owing to
incomplete development of functioning glomerular units. Beginning at about age 2
years, GFR normalizes for body surface area and gradually falls off with age as a
consequence of progressive loss of functioning nephrons.
GLOMERULAR FILTRATION
A high glomerular filtration rate is essential for maintaining stable and optimal
extracellular levels of solutes and water.
Qualitatively, the filtration of blood plasma by the renal glomeruli is the same as the
filtration of blood plasma across capillaries in other vascular beds. Glomerular
ultrafiltration results in the formation of a fluid with solute concentrations that are
similar to those in plasma water; the exceptions are proteins and other high molecularweight compounds, which are present at reduced concentration. The glomerular filtrate,
like filtrates formed across other body capillaries, is free of formed blood elements,
such as red and white blood cells.
Quantitatively, the filtration that occurs in the glomeruli greatly exceeds that in all the
other capillaries of the circulation combined. Compared with other organs, the kidneys
receive an extraordinarily large amount of blood flow—normalized to the mass of the
organ— and filter an unusually high fraction of this blood flow. Under normal
conditions, the glomerular filtration rate (GFR) of the two kidneys is 125 ml/min or 180
liters per day. Such a large rate of filtrate formation is required to expose the entire
extracellular fluid frequently (more than 10 times a day) to the scrutiny of the renaltubule epithelium. If it were not for such a high turnover of the extracellular fluid, only
small volumes of blood would be “cleared” of certain solutes and water per time unit.
Such a low clearance would have two harmful consequences for the renal excretion of
solutes that renal tubules cannot adequately secrete.
First, in the face of a sudden increase in the plasma level of a toxic material —
originating either from metabolism or food/fluid intake— the excretion of the material
would be delayed. A high blood flow and high GFR allow the kidneys to eliminate
harmful materials rapidly by filtration. A second consequence of low clearance would
be that steady-state plasma levels would be very high for waste materials that depend on
filtration for excretion. The following example by Robert Pitts, a major contributor to
renal physiology, illustrates the importance of this concept. Consider two individuals on
a diet that contains 70 g/day of protein, one with normal renal function (e.g., GFR of
180 liters/day), the other a renal patient with sharply reduced glomerular filtration (e.g.,
GFR of 18 liters/day). Each individual produces 12 g/day of nitrogen in the form of urea
(“urea nitrogen”) derived from dietary protein and must excrete this into the urine.
However, these two individuals achieve urea balance at very different blood urea levels.
We will make the simplifying assumption that the tubules neither absorb nor secrete
urea, so that only filtered urea can be excreted, and all filtered urea is excreted. The
normal individual can excrete 12 g/day of urea nitrogen from 180 liters of blood plasma
having a blood urea nitrogen of 12 g/180 liters, or 6.7 mg/dl. In the patient whose GFR
is reduced to 10% of normal, excreting 12 g/day of urea nitrogen requires that each of
the 18 liters of filtered blood plasma has a blood urea nitrogen that is 10 times higher, or
67 mg/dl. Thus, excreting the same amount of urea nitrogen —to maintain a steady state
—requires a much higher plasma blood urea nitrogen in the patient than in the normal
individual.
Equation 33-3
In the steady state, when metabolic production in muscle equals the urinary excretion
rate (UCrV) of creatinine, and both remain fairly constant, equation 33-3 predicts that a
plot of PCr versus CCr (i.e., PCr versus GFR) is rectangular hyperbola (Fig. 33-2). For
example, in a healthy person whose GFR is 100 ml/min, plasma creatinine is
approximately 1 mg/dl. The product of GFR (100 ml/min) and PCr (1 mg/dl) is thus 1
mg/min, which is the rate of both creatinine production and of creatinine excretion. If
GFR suddenly drops to 50 ml/min, the kidneys will initially filter and excrete less
creatinine, although the production rate is unchanged. As a result, the plasma creatinine
level will rise to a new steady state, which is reached at a PCr of 2 mg/dl. At this point,
the product of the reduced GFR (50 ml/min) and the elevated PCr (2 mg/dl) will again
equal 1 mg/min, the rate of endogenous production of creatinine. Similarly, if GFR
were to fall to one quarter of normal, PCr would rise to 4 mg/dl. This concept is
reflected in the right-rectangular hyperbola of Figure 33-2.
Figure 33-2. Dependence of plasma creatinine and blood urea nitrogen on
the glomerular filtration rate (GFR). In the steady state, the amount of
creatinine appearing in the urine per day (UcrV) equals the production rate.
Because all filtered creatinine (Pcr x Ccr) appears in the urine, (Pcr x Ccr)
equals (Ucr x V), which is constant. Thus, Pcr must increase as Ccr (i.e,
GFR) decreases, and vice versa. If we assume that the kidney handles urea
in the same way that it handles inulin, then a plot of blood urea nitrogen
versus GFR will have the same shape as that of creatinine concentration
versus GFR
Frequently, clinicians use the endogenous plasma concentration of creatinine, normally
1 mg/dl, as an instant index of GFR. This use rests on the inverse relationship between
the plasma creatinine concentration (PCr) and the creatinine clearance (CCr)