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GLOMERULAR FILTRATION
Measuring GFR
The glomerular filtration rate (GFR) can be measured
in humans by measuring the excretion and plasma
level of a substance that is freely filtered through the
glomeruli and neither secreted nor reabsorbed by the
tubules.
• Therefore, if the substance is designated by the letter
X, the GFR is equal to the concentration of X in urine
(UX) times the urine flow per unit of time (V.) divided
by the arterial plasma level of X (PX), or UXV./PX.
• This value is called the clearance of X (CX).
• PX is, of course, the same in all parts of the arterial
circulation, and if X is not metabolized to any extent in
the tissues, the level of X in peripheral venous plasma
can be substituted for the arterial plasma level
Substances Used to Measure GFR
• In addition to the requirement that it be freely filtered and neither
reabsorbed nor secreted in the tubules, a substance suitable for
measuring the GFR should be nontoxic and not metabolized by the
body.
• Inulin, a polymer of fructose with a molecular weight of 5200,
meets these criteria in humans and most animals and is extensively
used to measure GFR.
• Radioisotopes such as 51Cr-EDTA are also used, but inulin remains
the standard substance.
• In practice, a loading dose of inulin is administered intravenously,
followed by a sustaining infusion to keep the arterial plasma level
constant.
• After the inulin has equilibrated with body fluids, an accurately
timed urine specimen is collected and a plasma sample obtained
halfway through the collection.
•
Substances Used to Measure GFR
• Plasma and urinary inulin concentrations are
determined and the clearance calculated:
Uin = 35 mg /ml
V = 0.9 ml /min
Pin = 0.25 mg /ml
Cin= Uin* V/Pin =35*0.9/0.25=
In C= 126ml/min
Substances Used to Measure GFR
• clearance of creatinine (CCr) can also be used to determine
the GFR, but in humans, some creatinine is secreted by the
tubules and some may be reabsorbed.
• In addition, plasma creatinine determinations are
inaccurate at low creatinine levels because the method for
determining creatinine measures small amounts of other
plasma constituents.
• In spite of this, the clearance of endogenous creatinine is
frequently measured in patients.
• The values agree quite well with the GFR values measured
with inulin because, although the value for UCrV. is high as a
result of tubular secretion, the value for PCr is also high as a
result of nonspecific chromogens, and the errors thus tend
to cancel.
Normal GFR
• The GFR in an average-sized normal man is
approximately 125 mL/min.
• Its magnitude correlates fairly well with surface
area, but values in women are 10% lower than
those in men even after correction for surface
area.
• A rate of 125 mL/min is 7.5 L/h, or 180 L/d,
whereas the normal urine volume is about 1 L/d.
• Thus, 99% or more of the filtrate is normally
reabsorbed.
Control of GFR
• The factors governing filtration across the glomerular
capillaries are the same as those governing filtration across
all other capillaries , ie, the size of the capillary bed, the
permeability of the capillaries, and the hydrostatic and
osmotic pressure gradients across the capillary wall. For
each nephron:
GFR = Kf [(Pgc – Pt) – (πGC - πT ) ]
Kf, the glomerular ultrafiltration coefficient, is the product
of the glomerular capillary wall hydraulic conductivity (ie,
its permeability) and the effective filtration surface area.
PGC is the mean hydrostatic pressure in the glomerular
capillaries, PT the mean hydrostatic pressure in the tubule,
πGC the osmotic pressure of the plasma in the glomerular
capillaries, and πT the osmotic pressure of the filtrate in the
tubule.
Permeability
• The permeability of the glomerular capillaries is about 50 times that of the
capillaries in skeletal muscle.
• Neutral substances with effective molecular diameters of less than 4 nm
are freely filtered, and the filtration of neutral substances with diameters
of more than 8 nm approaches zero .
• Between these values, filtration is inversely proportionate to diameter.
• However, sialoproteins in the glomerular capillary wall are negatively
charged, and studies with anionically charged and cationically charged
dextrans indicate that the negative charges repel negatively charged
substances in blood, with the result that filtration of anionic substances 4
nm in diameter is less than half that of neutral substances of the same
size.
• This probably explains why albumin, with an effective molecular diameter
of approximately 7 nm, normally has a glomerular concentration only 0.2%
of its plasma concentration rather than the higher concentration that
would be expected on the basis of diameter alone; circulating albumin is
negatively charged.
• Filtration of cationic substances is greater than that of neutral substances.
Effect of electrical charge on the fractional clearance of dextran molecules of various
sizes in rats. The negative charges in the glomerular membrane retard the passage of
negatively charged molecules (anionic dextran) and facilitate the passage of positively
charged molecules (cationic dextran).
Permeability
• The amount of protein in the urine is normally
less than 100 mg/d, and most of this is not
filtered but comes from shed tubular cells.
• The presence of significant amounts of albumin
in the urine is called albuminuria.
• In nephritis, the negative charges in the
glomerular wall are dissipated, and albuminuria
can occur for this reason without an increase in
the size of the "pores" in the membrane.
Size of the Capillary Bed
• Kf can be altered by the mesangial cells, contraction of
these cells producing a decrease in Kf that is largely due
to a reduction in the area available for filtration.
• Contraction of points where the capillary loops
bifurcate probably shifts flow away from some of the
loops, and elsewhere, contracted mesangial cells
distort and encroach on the capillary lumen.
• Angiotensin II is an important regulator of mesangial
contraction, and there are angiotensin II receptors in
the glomeruli.
• In addition, there is some evidence that mesangial
cells make renin.
Agents causing contraction or
relaxation of mesangial cells.
Hydrostatic & Osmotic Pressure
• The pressure in the glomerular capillaries is higher
than that in other capillary beds because the afferent
arterioles are short, straight branches of the
interlobular arteries.
• Furthermore, the vessels "downstream" from the
glomeruli, the efferent arterioles, have a relatively high
resistance.
• The capillary hydrostatic pressure is opposed by the
hydrostatic pressure in Bowman's capsule.
• It is also opposed by the osmotic pressure gradient
across the glomerular capillaries (πGC - πT).
• πT is normally negligible, and the gradient is equal to
the oncotic pressure of the plasma proteins.
Hydrostatic & Osmotic Pressure
• The net filtration pressure (PUF) is 15 mm Hg at the
afferent end of the glomerular capillaries, but it falls to
zero—ie, filtration equilibrium is reached—proximal to
the efferent end of the glomerular capillaries.
• This is because fluid leaves the plasma and the oncotic
pressure rises as blood passes through the glomerular
capillaries.
• It is apparent that portions of the glomerular
capillaries do not normally contribute to the formation
of the glomerular ultrafiltrate; ie, exchange across the
glomerular capillaries is flow-limited rather than
diffusion-limited .
Changes in GFR
• Changes in renal vascular resistance as a result of
autoregulation tend to stabilize filtration
pressure, but when the mean systemic arterial
pressure drops below 90 mm Hg, there is a sharp
drop in GFR.
• The GFR tends to be maintained when efferent
arteriolar constriction is greater than afferent
constriction, but either type of constriction
decreases blood flow to the tubules.
Factors affecting the GFR
1.
2.
3.
4.
5.
6.
7.
8.
Changes in renal blood flow .
Changes in glomerular capillary hydrostatic pressure .
Changes in systemic blood pressure
Afferent or efferent arteriolar constriction
Changes in hydrostatic pressure in Bowman's capsule
Ureteral obstruction
Edema of kidney inside tight renal capsule
Changes in concentration of plasma proteins:
dehydration, hypoproteinemia, etc (minor factors)
9. Changes in Kf .
10. Changes in glomerular capillary permeability
11. Changes in effective filtration surface area
Filtration Fraction
• The ratio of the GFR to the renal plasma flow
(RPF), the filtration fraction, is normally 0.160.20.
• The GFR varies less than the RPF.
• When there is a fall in systemic blood
pressure, the GFR falls less than the RPF
because of efferent arteriolar constriction, and
consequently the filtration fraction rises.