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The glomerulus consists of a network of capillaries supplied by the afferent arteriole and is
drained by the efferent arteriole. The barrier to filtration is depicted in figure 2 and consists of
the endothelial lining of the capillary loop, the glomerular basement membrane and the slit
diaphragm of the podocytes. The glomerular barrier is highly specialized because of two
characteristics: 1) the effective pore size excludes molecules larger than 42 A. 2) because the slit
diaphragm and podocytes are negatively charged (glycoprotein composition), substances in the
blood with an effective molecular radius in the range of 20-42 A is selectively filtered: cationic
molecules are filtered more readily than anionic molecules. Therefore, charge is an important
and unique component of the permselective properties of the GBM. The glomerular ultrafiltrate
that enters Bowmans Space is an ultrafiltrate of plasma and contains no RBCs or albumin or
other proteins.
II.
GLOMERULAR FILTRATION
Glomerular filtration is the process that separates the aqueous phase of plasma from the
large proteins and formed elements. Like most capillaries, the glomerular capillaries are
relatively impermeable to large proteins, so the filtrate is relatively free of protein and absent
cellular components such as erythrocytes. The concentration of most ions and small molecules
in the glomerular filtrate mirrors that in the plasma except for drugs and substances bound in the
circulation to plasma proteins. About 20% of the blood plasma that flows through the glomeruli
is filtered, accounting for a glomerular filtration rate (GFR) in an adult human of about 125
ml/min or 180 L/day.
As in other capillaries, the flow across the capillary membrane is governed by the
Starling forces of hydraulic and oncotic pressures as well as the intrinsic permeability of the
membrane surface. This latter factor is called the hydraulic conductivity, or ultrafiltration
coefficient (Kf). The Kf of the glomerular capillary is 100-200 times greater than that in muscle
or other tissues so this helps account for the very high water permeability of these capillaries. In
addition, the pressure in the glomerular capillaries is higher than in systemic capillaries since it is
interposed between two arterioles that provide resistance. The hydraulic pressure in the
glomerular capillaries is about 50-60 mmHg while that in peripheral muscle averages only 10
mmHg or 20.
There is also a structural difference between the glomerular capillaries and others
throughout the body, since in the kidney there are three layers instead of the usual two. The
capillary has an endothelium that is punctuated by fenestrations, a basement membrane, and then
a layer of epithelial cells known as podocytes. Each of these three layers contributes to the
filtration barrier since natural or induced diseases in which molecular components of these
membranes are perturbed results in a loss of the permselective properties of this barrier and
leakiness to larger molecules such as protein.
Figure 1
Figure 2
Glomerular filtration is a special case because the filtered fluid enters the tubule lumen
rather than re-entering the glomerular capillaries. The essential features of the process are shown
in Figure 3:
1.
The top line is glomerular capillary hydrostatic pressure (PGC); equal to approximately 55
mmHg (depending upon species). In contrast to the peripheral capillary bed, PGC does not
decrease significantly along the length of the glomerular capillary. This is because the
glomerular capillary is positioned between two high resistances (afferent and efferent
arterioles).
2.
3.
Plasma oncotic pressure is 22 mmHg at the beginning of the capillary. Therefore, the net
ultrafiltration pressure is about 18 mmHg at the beginning of the capillary (shaded).
4.
Colloid osmotic pressure increases along the length of the capillary as water and
electrolytes are filtered and removed (thereby increasing protein concentration). Note
that ultrafiltration pressure declines in glomerular capillaries mainly because plasma
oncotic pressure rises, not because of a decrease in intracapillary hydrostatic pressure, as
in systemic capillaries.
5.
The single nephron glomerular filtration rate can therefore be described as:
a. SNGFR = Kf ([PG PBS] COP)
Figure 3
To summarize, the unique differences between glomerular capillaries and peripheral capillaries
are as follows:
1.
Glomerular capillaries have a high hydraulic conductivity.
2.
Glomerular capillaries are located between two high resistances, which minimize the
pressure drop along the length of the capillary, and are highly regulated. Pressure is
higher than in other capillary beds.
I.
In order for fluid to be reabsorbed, as in the venular end of the peripheral capillary,
hydrostatic pressure must fall below that of oncotic pressure. This situation occurs in the
postglomerular, peritubular circulation of the kidney, those capillaries which surround the renal
tubules. However, before considering peritubular capillary circulation, let us consider the overall
problem facing peritubular capillaries.
Figure 4 and subsequent diagrams show the following structures contained in a unit
nephron:
1.
2.
3.
4.
afferent arteriole
glomerular capillary
efferent arteriole
peritubular capillary. Notice that blood perfusing peritubular capillaries is post
glomerular.
5.
Figure 4
These approximate normal values for humans
Given the quantities shown in the figure:
3. Efferent glomerular plasma flow (QE) is 480 ml/min
4. The ratio of GFR to QA (filtration fraction, FF) is 0.2
5. Tubular reabsorption of filtrate is 99.5% of amount filtered
6. The volume of urine excreted is only 0.5% of the volume of fluid filtered
7. Therefore, peritubular capillaries must reabsorb 99.5% of the fluid filtered through
glomeruli. This is intuitively clear because the huge volume of fluid filtered at the
glomerulus would quickly deplete the body of water if reabsorption were not
extensive and efficient. The process of water reabsorption into the peritubular
capillaries from the renal interstitial compartment involves the same forces already
outlined which govern fluid movements in all capillaries. The process by which
glomerular filtrate passes across the cells of renal tubular epithelium involves
different forces, which will be discussed in a later section.
Figure 5 illustrates the profile of forces that govern fluid uptake by the peritubular
capillaries. Fluid movement is from interstitium into capillary, the reverse of glomerular
filtration. As we saw in the previous diagram, these capillaries are post glomerular in derivation;
i.e., the blood has passed through the glomerulus and efferent arteriole. Therefore, at the
beginning of the peritubular capillary, colloid osmotic (oncotic) pressure is higher than in the
systemic circulation, and is approximately the same as at the end of the glomerular capillary or
about 40 mmHg. The line shown in this diagram is the net colloid osmotic pressure, which is the
difference between the intracapillary colloid osmotic pressure and the interstitial colloid osmotic
pressure. Interstitial colloid osmotic pressure is due to a small amount of lymph protein in the
interstitial fluid and averages about 7mmHg. Net colloid osmotic pressure falls along the length
of the capillary as protein-free fluid is absorbed from the interstitium back into the capillary.
Figure 5
Peritubular capillary hydrostatic pressure HP is low, since these capillaries lie beyond the
high resistance in the efferent arteriole, averages around 11 mmHg, and is balanced by a positive
hydrostatic pressure in the renal interstitium equal to 6.5 mmHg. Therefore, net hydrostatic
pressure across the peritubular capillary wall is 4.5 mmHg.
The shaded area between these lines for net colloid osmotic pressure and net HP
represents the net driving force for uptake of fluid from renal interstitium to capillary. It is the
difference between net colloid osmotic pressure favoring reabsorption and net hydrostatic
pressure retarding it.
There is a net driving force of about 30 mmHg moving fluid from the interstitial
compartment into the capillary at the beginning of the capillary. This driving force declines to
about 15 mmHg at the venular end of the capillary.
Summary:
The renal tubule transports a large amount of fluid into the interstitial compartment which
must be returned to the circulation via peritubular capillaries. Therefore, peritubular capillaries
must reabsorb a large amount of fluid from the interstitial space. This process is facilitated by
two features of the renal circulation that cause conditions in the peritubular capillaries to be
similar to the venular end of peripheral capillaries.
1.
Peritubular capillary hydrostatic pressure is low because it lies beyond a high resistance
in the efferent arteriole.
2.
Colloid osmotic pressure of peritubular capillary blood is high because the blood is
postglomerular. In other words, as blood flows through glomerular capillaries, proteinfree fluid is removed from blood and passes into the tubule. During passage down the
tubule, most of the fluid is transported out of the tubules and into the interstitial fluid
compartment, where it is returned to the circulation via the peritubular capillaries. The
volume of this large fluid turnover is approximately equivalent to the GFR, which in
normal man is 120 ml/min, about 2% of the cardiac output. This unique feature of the
renal vascular bed provides a considerable flexibility to the kidney in the formation of
urine, as we shall see.
II.
CLEARANCE CONCEPT
To consider a method for measurement of the glomerular filtration rate (GFR), we need
to appreciate the most important single tool in the overall assessment of renal function; i.e., the
clearance concept which is illustrated in Figure 6.
The kidney removes certain substances from blood and excretes them in urine.
Therefore, blood is cleared of these substances. The clearance concept allows one to calculate
the volume of blood cleared of a given substance per unit time.
Measurement of GFR is a special case of the clearance technique. It is performed by
measuring the clearance of a substance filtered by the glomerulus, but is neither reabsorbed nor
secreted by the tubule. The prototype of such a substance is the complex polysaccharide, inulin.
In Figure 6, Z is such a substance. The concentration of Z in plasma (PZ) is 10 mg/ml. If
the GFR is 120 ml/min, the amount of Z filtered (or filtered load of Z) is 120 x 10 or 1200
mg/min.
Figure 6
As fluid passes down the tubule, water is reabsorbed, but not Z. Therefore, the amount of
Z excreted is exactly the same as the amount filtered. Remember that
Amount = Volume x Concentration
The amount of Z excreted is UZV; the amount filtered is GFR x PZ. Therefore, these two
quantities are equal, as shown by equation 1 in Figure 6. Solving equation 1 for GFR gives
equation 2. GFR equals excretion rate of Z (UZV) divided by plasma concentration (PZ). The
units are in ml/min. The parameters of this equation are easily measured.
Equation 2 is a clearance equation, which is written in a general form in equation 3.
Equation 3 is valid for any substance cleared from blood by the kidney. The clearance of any
substance is equal to the excretion rate of the substance divided by the plasma level of the
substance.
These calculations are illustrated in Figure 7. Clearance of any substance Z is equal to excretion
rate divided by plasma concentration. Units are ml/min.
CLEARANCE (C)
Clearance of substance Z
UZV
PZ
UZ = Urine concentration of Z (mg/ml)
PZ = Plasma concentration of Z (mg/ml)
V = Urine flow (ml/min)
C =
C=
mg/ml x ml/min
mg/ml
C=
(ml/min)
Figure 7
Clearance in ml/min is the volume of plasma completely cleared of substance Z per unit
time. Volume in this expression is a virtual volume, not a real volume, since the kidney cannot
completely remove any substance from a partial volume of a well-mixed solution such as
plasma. However, the net physiologic effect with regard to any substance cleared by the kidney
is as though a subfraction of plasma were completely cleared of the substance per unit of time.
To take the example of the preceding figure, inulin (substance Z) clearance is 120
ml/min. This means that the net physiologic effect of renal function is to remove all inulin that
would have been contained in 120 ml of plasma each minute. As mentioned earlier, this same
concept applies to any substance cleared by the kidney, which includes almost every substance
present in plasma water.
The normal inulin clearance (GFR) in adult humans between the ages of 20 and 50 is 122
13 ml/min. The GFR in males tends to be higher than females, and it usually declines with age
in both sexes. The identity of inulin clearance and GFR as shown in the previous diagram
depends on certain assumptions, the most important of which is that the amount of inulin filtered
is equal to the amount excreted. A drawback to the routine clinical use of inulin clearance to
measure GFR is that a sterile solution must be infused at a constant rate and accurately times
urine collections made. Blood must be sampled to ensure steady state. Nevertheless, it remains
the gold standard.
Creatinine, an endogenous metabolite, is a useful as a marker of GFR, becaue the plasma
level is relatively constant and does not have to be infused. Creatinine is excreted mostly, but
not totally, by glomerular filtration so that its clearance approximates that of inulin. Therefore,
for a clinical estimate of GFR, the endogenous creatinine clearance may be used.
Because creatinine is produced endogenously at a relatively constant rate unless big
changes in muscle metabolism occur, the plasma or serum level of creatinine can also be used as
an index of renal function. If GFR is reduced by 50% with constant production, serum creatinine
will double. Thus, it serves as an easy clinical marker of kidney function. Since in the clinical
setting a 24 hour collection is often used, it is not surprising that the accuracy of the Ccr depends
on whether all urine is collected appropriately. The error rate is high and therefore this test is
used less often. Figure 8 illustrates the reverse hyperbolic relationship between serum creatinine
and GFR. Note that the major limitation of the serum creatinine is its insensitivity to small
changes in GFR in the range of 50-100 mL/min.
Figure 8
Because of collection errors and inconvenience, one nomogram for estimating GFR just
from the serum creatinine concentration, age, sex, and weight, is known as the Cockcroft-Gault
formula:
GFR (males) =
GFR (females) =
In our hospital and in most clinical reference laboratories used by physician offices
throughout the US, the plasma or serum creatinine can be used to calculate an estimated GFR or
eGFR, using the MDRD study equation (see below). Every serum creatinine measured in
clinical practices of WFBH is accompanied by an automated calculation of eGFR. While only
accurate for calculation of GFR < 60 mL/min, and only applicable for adults, the eGFR
calculated in this way is much more accurate than relying on a Pcr alone, and has been shown to
help the clinician detect kidney disease at an earlier stage. The MDRD equation helps the
clinician recognize clinical kidney disease before the Pcr increases significantly. Note in figure 8
that the Pcr may not increase until the GFR is less than 70 mL/min in many patients.
MDRD Formula for eGFR:
GFR (ml/min/1.73m2) = 186 x (Pcr)-1.154 x (Age) -0.203 x (0.742 if female) x (1.210 if African
American)
The equation requires 4 variables: plasma creatinine age sex African American or not
Occasionally a radioactively tagged compound is used to estimate GFR by its clearance.
Some examples are 131I-iothalamate, 51Cr-EDTA, or 99mTcDTPA.
Figure 9
Note: try to understand fluid and solute movement in the renal tubules. These processes
as summarized above are diagramed conceptually in Figure 9.
Figure 10 considers the clearance of a substance that is filtered and reabsorbed by the
tubules.
Figure 10
In this example consider a substance (A) for which 80% of the filtered load is reabsorbed
by the tubules. GFR is the same as in Figure 6, 120 ml/min. The plasma level of substance A is
10 mg/ml. Therefore, the filtered load is 1200 mg/min. Since 80% is reabsorbed, 960 mg/min is
reabsorbed, and 240 mg/min excreted. Therefore, the clearance of A is 240 10 or 24 ml/min.
Note that the clearance of A can be measured without knowing GFR. However, one
cannot calculate the amount of A reabsorbed by the tubules without knowing the GFR since it is
necessary to calculate the filtered load.
Figure 10 illustrates the relationships among the various types of substances handled by
the kidney and serves to summarize the preceding discussion.
The clearance of a substance filtered and reabsorbed (A) will always be less than the
clearance of inulin. The clearance of a substance filtered and secreted, but not reabsorbed,
is greater than the clearance of inulin.
The kidneys, which constitute only 0.5% of the total body weight, receive approximately
25% of the cardiac output. The total renal blood flow per gram of tissue is one of the highest in
the body. As we have seen in the previous section, plasma water is filtered from the blood
through glomeruli and returned to the blood by tubular reabsorption. Thus, the kidney is unique
in having a large blood flow and a high fluid turnover within the organ itself.
III.
Total renal blood flow in humans (both kidneys) is approximately 1100 ml/min. There
are basically two ways to measure total renal blood flow:
1.
Electromagnetic (EM) or Doppler flow probe. The most accurate measurement of renal
blood flow is obtained by these devices. The EM probe is a device which senses the
electrical changes produced by blood as it flows through a vessel and with proper
calibration can measure flow very precisely, but attaching a flow probe to a renal artery is
obviously restricts its use to animal studies. The pulsed Doppler device measures the shift
in ultrasound echo produced by flowing blood, and modifications of Doppler technology
allow transcutaneous measurements. We have an excellent Vascular Laboratory at
WFBH using the latter technique for evaluation of RBF and comparison of left and right
RA values. Such a technique is very helpful to exclude the diagnosis or renal artery
stenosis.
2.
Clearance of a flow dependent substance. The second method for estimating total blood
flow involves use of the indirect Fick method, which you have previously encountered in
lectures on other circulatory beds.
Flow (ml/min) =
Consumption (mg/min)
(A-V) (mg/ml)
If there were a substance cleared by the kidney for which the renal venous concentration
approached zero (Figure 11), it would simplify the equation. Such a substance would be one
removed completely in one pass through the kidney. It turns out that substances which are
secreted by the renal tubules, such as organic acids and bases, fulfill this requirement. PAH (paminohippurate) is such a substance.
Figure 11
Accordingly, using PAH as the marker, the venous concentration approaches zero and the
venous term can be dropped from equation 4, yielding equation 5. You should recognize
equation 5 as the familiar clearance equation; i.e., urinary excretion rate of PAH divided by its
plasma concentration. Thus, the clearance of PAH and substances handled in a similar fashion
by the kidney provides an approximation of renal plasma flow.
IV.
INTRARENAL HEMODYNAMICS
Figure 12
Figure 13
If RE decreases, the ratio RA/RE increases, glomerular pressure decreases, GFR goes down, and
RBF rises. If RE increases, the converse occurs. Thus, changes in RA cause GFR and RBF to
change in opposite directions.
If RA and RE both increased an equivalent amount, so that the ratio RA/RE were
unchanged, RBF would decrease but glomerular pressure would remain the same and GFR
would not decrease.
Mesangial cells in the glomerulus can also constrict or dilate in response to certain
vasoregulatory hormones and peptides. Constriction by the mesangium lowers surface area and
Kf and in this manner may also serve as a regulator of GFR.
A number of endogenous vasoactive substances regulate renal resistance. Some are listed
in Table 1.
Table 1
Some Regulators of Renal Arteriolar Tone
Constrictors
Dilators
Andenosine
Bradykinin
Angiotensin II
Nitric oxide
Endothelin
Prostaglandins
Norepinephrine
V.
A major determinant of flow is perfusion pressure, as shown in Figure 14. This diagram
illustrates the consequences of changes in renal perfusion pressure. Renal arterial pressure is on
the abscissa, and RPF and GFR and on the ordinate. Between 80 and about 200 mmHg MAP,
there is almost no change in either GFR or RPF. This phenomenon is defined as autoregulation.
Autoregulation is a phenomenon whereby increases or decreases in perfusion pressure cause no
changes in GFR or RBF. Autoregulation is probably due to changes in RA, such that when
perfusion pressure falls, vasodilation occurs in the afferent arteriole; and when perfusion pressure
rises, the reverse occurs. Remember, changes in RA cause GFR and RPF to change in the same
direction, so that changes in RA could account for regulation of both GFR and RPF.
Figure 14
Because GFR and RBF are both regulated over the same pressure range, and because
renal plasma flow is an important determinant of GFR, the same mechanisms appear to regulate
both flows. Note that when MAP drops below the autoregulatory range, both GFR and RBF
drop dramatically. Consider hypotension and acute renal failure (ARF).
Two mechanisms are responsible for autoregulation of RBF and GFR: one that responds
to changes in arterial pressure and one that responds to changes in tubular flow rate.
1.
2.
The macula densa (MD) is the segment of the distal convoluted tubule that contacts the
afferent arteriole of its own glomerulus. The conjunction of the two structures is called the
juxtaglomerular (JG) apparatus (Figure 15). An increase in NaCl delivery to the MD elicits
release of a vasoconstrictor (angiotension), which causes afferent arteriolar vasoconstriction, as
shown in Figure 16.
Figure 15
Figure 16
According to this paradigm an increase in renal perfusion pressure would increase GFR,
causing increased delivery of NaCl to the MD. This would cause increased release of
vasoconstrictors, which would then cause an increase in RA and thus decrease (or restore) PGC.
Vasoactive hormones such as some of those listed in Table 1 or some drugs that block the
transport-related signal at the macula densa can interrupt the myogenic and TGF pathways to
change renal resistance and GFR for a given level of perfusion pressure.
Outside the context of autoregulation, a major influence on RA and probably RE is the
sympathetic nervous system. Afferent arterioles are innervated by adrenergic fibers, and
increases in SNS activity can clearly cause an increase in RA. However, autoregulation occurs
even in denervated kidneys. Therefore, renal nerves modulate but are not solely responsible for
autoregulation.
Finally, there is another potentially important regulator of renal blood flow to appreciate,
the prostaglandins. Prostaglandins are a family of fatty acids produced in all blood vessels and
other cells of the body, which have a wide array of biologic activities. Of interest is that
prostacyclin (PGI2) is produced in renal blood vessels, especially in the cortex, and that E series
prostaglandins are produced in the renal medulla. They are both potent renal vasodilators. Some
prostanoids such as thromboxanes and products of cytochrome P450 are vasoconstrictors and may
play a role in autoregulation and renal pathology. However, there is good evidence that
prostaglandins together with renin are responsible for maintenance of the pattern of intrarenal
blood flow distribution discussed earlier. The vasodilatory prostaglandins do not participate
meaningfully in the maintenance of GFR under normal circumstances, but can be very important
in militating against the effect of vasoconstrictors. Numerous studies have shown that the
interaction of the vasoconstrictors (norepinephrine, etc.) and the vasodilatory prostaglandins help
to maintain RBF and GFR in clinical circumstances such as shock and volume depletion. The
ability to mitigate the effect of vasoconstrictors is significantly impaired if prostaglandin
production is inhibited by drugs such as non-steroidal anti-inflammatory drugs (NSAIDS) (e.g.
ibuprofen, etc.). Accordingly, vasoconstriction then proceeds unabated and acute renal failure
may ensue. Since the use of NSAIDs is so common, they often play a role in the susceptibility
of certain categories of patients to develop acute renal failure especially in circumstances
associated with vasoconstriction, such as shock from blood loss or sepsis. Categories of patients
at risk for NSAID-induced ARF include patients with preexisting CKD, diabetics, and the
elderly.