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What is the filtration fraction? What are some typical numbers for its components? Why is GFR so high compared to other capillary beds ?

In normal resting man the glomerular filtration rate (GFR)
averages 125 mL/min. The ultrafiltrate is derived from an averagetotal renal plasma flow (RPF) of 600 mL/min. The ratio ofGFR to RPF is referred to as the filtration fraction (FF):


The FF represents the fraction of plasma that is filtered across
the glomerular capillary bed. Alterations in the FF can have an important effect on proximal tubular reabsorption of fluid.
The GFR is several fold higher than filtration in other capillary
beds because the surface area plus the permeability of the
glomerular capillary membrane is greater than 100-fold that
of other capillary beds


What determines GFR or what drives it? Waht indirectly modulates GFR?

The net filtration across the glomerular capillary bed is governed
by the algebraic sum of hydrostatic and oncotic pressures
across the capillary wall (Fig. 4.2).
The GFR can be derived from the following mathematical

GFR=Kf x (Pgc-Pbs) - (Pigc-Pibs)

where Kf equals the membrane permeability × surface area;
PGC equals the hydrostatic pressure in the glomerular capillary; PBS equals Bowman’s space pressure; πGC equals the glomerular
capillary oncotic pressure; πBS equals Bowman’s space
oncotic pressure; ΔP equals the transcapillary hydrostatic
pressure (PGC – PBS); Δπ equals the transcapillary oncotic
pressure (πGC – πBS) and PUF is the net ultrafiltration pressure
(indicated by the blue area in Fig. 4.3). All pressures are
expressed as mean values (note overstrikes in Eq. [4.2]) to
account for pressure changes along the glomerular capillary
(see Fig. 4.3).
Since the glomerular ultrafiltrate is typically protein free,
πBS is equal to zero, and, therefore, the oncotic pressure in
Bowman's space is usually excluded from the above analysis.
Accordingly, the major direct determinants of GFR include
• PGC (mm Hg)
• PBS (mm Hg)
• Kf (nL/s/mm Hg)
• πGC (mm Hg)
In addition to the direct determinants of GFR, RPF also
indirectly modulates GFR and will be discussed below.


What are the two factors that Pgc is dependent on? How does Pgc affect GFR? Why don't patients with systemic hypertension present with increased GFR?

The PGC is dependent on two factors:
1. The systemic blood pressure (an increase in blood
pressure will increase PGC as long as the ratio of the
resistance in the afferent arteriole (AA) and efferent
arteriole (EA) remains constant).
2. The ratio of the resistance in the AA (RA) versus EA
(RE) (an increase in RA/RE will decrease PGC provided the
systemic blood pressure remains unchanged).

An increase in PGC will increase GFR while decreases result
in a fall in GFR. It is important to note that there is only a 2-4 mm
Hg change in glomerular pressure from the beginning to the
end of the capillary (mean PGC = 50 mm Hg). Thus, the glomerular
capillary is a low-resistance vascular bed. However, the
glomerular capillary network is juxtaposed between two highresistance
muscular arterioles (afferent arteriole, AA, and
efferent arteriole, EA). This vascular arrangement allows for
precise control of RBF and GFR (Fig. 4.4) and plays a crucial
role in the physiological regulation of GFR and RBF in various
clinical disease states. For example, physiological changes in
the ratio of AA to EA resistance permit maintenance of RBF
and GFR when perfusion pressure to the kidney is reduced.

Patients with systemic hypertension do not typically
present with an increased GFR because the RA increases
and prevents the systemic pressure from being transmitted
to the glomerular capillary (PGC remains unchanged).


What can affect Kf and what effect does Kf have on GFR?

The glomerular mesangium contains contractile cells that are
believed to regulate glomerular surface area (and hence Kf)
by closing (contraction) or opening (relaxation) glomerular
capillaries to which they are tethered. Contractile mesangial
cells ultrastructurally appear to be anchored to the EA, perhaps
underscoring their role in regulating GFR. As expected,
increases in Kf will increase GFR while a fall in Kf will reduce
GFR. Although beyond the scope of this discussion, the exact
change in GFR in response to alterations in Kf is dependent on
the whether filtration equilibrium versus disequilibrium exists.


What can effect Pbs and how does this effect GFR? Give clinical examples.

Bowman’s space pressure remains constant (mean pressure =
10-12 mm Hg) because of unimpeded flow of glomerular filtrate.
An obstruction to urinary outflow distal to Bowman’s
space will result in a fall in ΔP (and hence GFR) because of a
rise in Bowman’s space pressure.

Patients with urinary tract obstruction secondary to
cancer, stones, or prostatic enlargement may present with
profound reductions in GFR. Renal function can often be
restored following removal of the obstructing lesion.


Describe how Pigc affects GFR? How does this change throughout the length of the capillary?

The glomerular capillary oncotic pressure is the principle factor
opposing glomerular filtration. Because the ultrafiltrate is protein
free, the oncotic pressure rises nonlinearly along the length
of the glomerular capillary. Therefore, the rate of glomerular
filtration gradually decreases (see Fig. 4.3). Direct measurements
of glomerular hemodynamics in the rat and dog have
demonstrated that glomerular capillary oncotic pressure counterbalances
the hydrostatic pressure in the glomerular capillary
prior to the end of the capillary. This phenomenon is referred to
as filtration equilibrium because filtration ceases at this point.


Through what mechanism does RPF modulate GFR?

In conditions characterized by an increase in renal plasma
flow, filtration equilibrium is shifted distally along the capillary
bed resulting in an increase in PUF (blue-shaded area)
and increases GFR. RBF, thus, modulates GFR by altering the
oncotic pressure profile (Fig. 4.5) or mean oncotic pressure
(see Eq. [4.2]).


How is RBF modulated? What modulates its components?

The regulation of RBF is mediated by changes in renal vascular
resistance and is described by the following relationship:

RBF=Renal Perfusion Pressure/Renal Vascular Resistance
where, the renal perfusion pressure is the difference between
systemic pressure and renal venous pressure, and renal vascular
resistance (RVR) is primarily a consequence of arteriolar
tone in the afferent and efferent arterioles. Indeed, 85% of the
total RVR is secondary to the vascular tone in the afferent and
efferent arterioles.


Explain Renal autoregulation. What is its purpose? What is an example of how its limits might be exceeded? What are three mechanisms that control it?

Although Eq. (4.3) predicts a linear increase in RBF in response
to an increase in perfusion pressure, the RBF (and GFR)
remain remarkably constant over a wide range of systemic
arterial pressures (Fig. 4.6). This phenomenon is referred to as
autoregulation. The physiological significance of autoregulation
is to maintain RBF, GFR, and solute excretion relatively
constant during normal day-to-day variations in posture and
exercise which tend to alter systemic pressure and renal perfusion.
However, it is essential to recognize that autoregulation
has limits, which can be exceeded under specific clinical circumstances such as following severe volume contraction,
for example, hemorrhage or dehydration (see Fig. 4.9).
There are three major mechanisms that have been postulated
to contribute to the phenomenon of autoregulation:
1. Myogenic stretch
2. Tubuloglomerular feedback
3. Changes in the activity of the renin-angiotensin system


What happens in the myogenic stretch reflex? How might this happen?

The myogenic mechanism is similar to that described in other
autoregulating vascular beds. In response to a decrease in perfusion
pressure the afferent arteriole vasodilates and attenuates
the fall in RBF and GFR. The opposite sequence of events
occurs following an elevation in renal perfusion pressure (as
might occur with systemic hypertension). The cellular mechanism
may involve variable entry of Ca2+ into cells.


Describe the purpose and mechanism of tubuloglomerular feedback.

Tubuloglomerular Feedback
Tubuloglomerular feedback (TGF) is an intrinsic feedback loop
designed to protect against large fluctuations in solute excretion For example, an increase in renal perfusion pressure
would tend to augment PGC and RBF. These factors, in turn,
elevate the GFR. An increase in GFR would increase urine flow
and solute excretion. Unabated, this could result in significant
(even life-threatening) solute and water losses in the urine.
However, the macula densa cells of the distal nephron sense
changes in delivery of NaCl or water resulting in the release
of a potent renal afferent arteriolar vasoconstrictor (likely
adenosine). This “brake” mechanism appropriately inhibits the
increase in GFR and solute excretion by constricting the afferent
arteriole and returning the RBF and PGC to normal.


What roles does TGF play in ATI? What role does it play normally?

TGF may play an important role in the prevention of
potentially life-threatening fluid losses after injury to the
renal tubular reabsorptive epithelium (also known as
acute tubular Injury , ATI). For example, aminoglycoside
antibiotics commonly injure the proximal tubular
epithelium and could precipitate massive fluid losses
(given the large volume of fluid normally reabsorbed by
the proximal tubule). However, activation of TGF would
decrease GFR and RBF of the parent glomerulus decreasing
filtration (and fluid losses). Interestingly, disorders that
result in proximal tubular epithelial injury are invariably
associated with profound (? protective) reductions in GFR

Although TGF may play a protective role in certain clinical
disorders (acute tubular injury), its general role in the
maintenance of normal renal function remains poorly understood.
Several unknowns such as the variable that is sensed
at the macula densa (solutes, water, or both) and the effectors’
that elicits changes in arteriolar tone (adenosine) have
remained controversial. In general, TGF is thought to protect
against fluctuations in GFR and RBF in the face of day-to-day
variations in GFR and solute excretion that would occur with
a change in posture or exercise..


What is the purpose of the RAS? What triggers renin release? What is the mechanism after that? What are the effects of it on the tubular system?

The renin-angiotensin system (RAS) is activated by stretch
receptors in the afferent arteriole of the juxtaglomerular apparatus
resulting in the release of the enzyme renin. Renin ultimately
leads to the synthesis of angiotensin II. Angiotensin II
is a potent renal vasoconstrictor that preferentially constricts
the EA. A rise in efferent arteriolar tone raises PGC that, in turn,
increases GFR. The increase in GFR tends to offset the reduction
in RBF that would occur because of an increase in RVR
induced by EA vasoconstriction. Renin release by the kidney
can also be modulated by the sympathetic nervous system since the JG apparatus of the AA is innervated by β-adrenergic
fibers. Activation of the nerves innervating the kidney or an
increased circulating level of catecholamines elicits an increase
in renin release from the granular cells of the AA.

44 C L I N I C A L CO R R E L AT I O N
Volume contraction evokes avid NaCl and water retention
by the kidney. The decrease in distal flow rate produces an
increase in circulating renin and angiotensin II (mediated
through the macula densa cells). An increase in angiotensin
II directly promotes NaCl and water reabsorption in the
proximal tubule. This effect restores arterial blood volume
and pressure toward normal.


How and when might autoregulation fail? What prevents renal ischemia in these cases?

It is important to appreciate that despite autoregulation, RBF
and GFR can substantially vary from normal when certain conditions
exceed the limits of “normal” autoregulation (Fig. 4.9).
For example, the afferent and efferent arterioles are richly
innervated with α1-adrenergic receptors. These receptors are
activated by the sympathetic nervous system. Catecholamines potently vasoconstrict the renal vasculature and override the
autoregulatory system, ultimately producing a decrease in RBF
and GFR. A variety of relatively common clinical conditions
can override autoregulation. These include severe volume contraction,
significant hemorrhage, severe heart failure, or shock.

Interestingly, counterregulatory mechanisms (vasodilator
prostaglandins) appear to “brake” this response, thus, preventing or
minimizing renal injury secondary to ischemia. An important clinical
pearl to derive from this response is that renal autoregulation can be
exceeded when the intact organism is subjected to a severe clinical insult.
In this case the systemic blood pressure is maintained at the expense of
a decrease in GFR and RBF. However, the “counterregulatory mechanism”
minimizes (hopefully prevents) organ injury secondary to renal ischemia.