Kidneys, Ureters, and Suprarenal Glands

Renal #9
Tues, 03/18/03, 11am
Dr. Mallet
Jennifer Uxer for Jennifer Derby
Page 1 of 9
Glomular Filtration
Note: The beginning of this lecture wrapped up the introductory lecture from Monday.
Some figures have been included in this scribe because that was the best way to
describe what was said in class. Other figures were not included because word
descriptions were sufficient. Be sure to look at these in the powerpoints.
 Clearance describes how effectively the kidneys remove a substance from the
bloodstream and excrete it in the urine
A. Calculation of Clearance
 Clearance of substance X = concentration of X in urine * urine volume
concentration of X in plasma
CX = (UX * V)/PX
 Example: urea
Purea = 20 mM
Uurea = 400 mM
V = 1 ml/min
Curea = (400 mM * 1 ml/min)/20mM = 20 ml/min
Note the units: volume per unit time (ml/min)
B. GFR can be determined from clearance of certain compounds
 Requirements: compound must be freely filtered, but neither secreted nor
 If these requirements are met: The amount filtered = amount excreted, then
the GFR = the clearance: GFR * PX = UX * V
 Rearranging, we find:
GFR = (UX * V)/ PX = CX In reality, this isn’t true for any
compound in the body.
C. Inulin clearance
 Inulin clearance = GFR
 Inulin isn’t found in the body; it’s a fructose polysaccharide that must be
infused. So, it’s not practical for clinical use.
 Inulin: freely filtered, neither reabsorbed, secreted nor metabolized
 Amount inulin filtered per unit time = amount excreted per unit time.
GFR * Pin = Uin * V Rearranging: GFR = (Uin * V)/Pin = Cin
D. Creatinine
 Use of inulin is cumbersome; creatinine is produced endogenously (muscle
metabolite), so no infusion is needed. It behaves a lot like inulin.
 All filtered creatinine is excreted. Some is secreted in the proximal tubule
causing an overestimation of GFR because the numerator is a bit too high.
Glucose and other stubstances causes over estimation of creatinine in the
plasma. So the 2 overestimations cancel out.
 The two sources of error nearly cancel out, so Ccrt = (Ucrt x V)/Pcrt ~GFR
 This is difficult to use clinically because you have to depend on patient
compliance to collect all their urine over a period of time.
E. Pcrt monitors renal function (see B&L Fig. 40-12, p. 688)
 Pcrt (plasma creatinine concentration) is inversely proportional to GFR
Renal #9
Tues, 03/18/03, 11am
Dr. Mallet
Jennifer Uxer for Jennifer Derby
Page 2 of 9
Theoretically, if GFR falls to 25% of normal (there’s ¼ of the renal mass
remaining), Pcrt should increase fourfold
 In reality, inverse relationship isn’t perfect:
– Differences in lean muscle mass—more lean muscle = more creatinine.
– Compensatory increased proximal tubule secretion of creatinine when
the kidneys begin to fail. This decreases the plasma [creatinine].
 Useful: long-term monitoring of renal function. If you have diabetic
patients, you’d like to know when they begin to experience kidney failure.
Taking blood samples over time will provide this information: if GFR falls,
creatinine begins to accumulate in the blood.
 Pcrt vs. GFR: the ideal and the real—see ppts for the plots. These are graphs
of the theoretical plasma creatinine vs. the glomerular filtration rate in a
healthy, young male. This is about 1mg/dL of creatinine per 180L/day
(GFR) As renal function declines and GFR declines, creatinine will go up.
In reality (right plot), the plot is shifted to the left and down, relative to the
theoretical plot, due to the compensatory secretion in the proximal tubule.
Additionally, the values are scattered for different people. The trend is the
same, though. If there’s an increase in creatinine, you can identify
renal failure. For example, an increase from 1 to 3 mg/dL indicates a
tremendous decline in GFR and a loss of about 90% of the nephrons.
F. PAH clearance estimates renal plasma flow—the total volume of plasma flow
through the kidneys
 Para-amino hippuric acid (PAH):
– Is an artificial drug and is a small molecule.
– Freely filtered
– Avidly secreted in proximal tubule
– If the PAH concentration is low, the nephrons can remove all of the
PAH from the kidneys.
 PAH is completely cleared from peritubular capillaries when the
concentration of PAH is low (i.e. when it is NOT saturated)
 For the exam, assume that the PAH clearance = renal plasma flow
because there’s a LOW concentration of PAH.
SUMMARY: Key information from session 1
 Nephron segments and where they are located
 Renal microcirculation is unique: 2 sets of arterioles and capillaries in series
 Sympathetic innervation provides for arteriole constriction and renin secretion
 Basic processes of urine formation: glomerular filtration, tubular reabsorption
and secretion, urinary excretion
 Clearance: (U * V)/P This can be used to estimate GFR and renal flow.
Renal #9
Tues, 03/18/03, 11am
Dr. Mallet
Jennifer Uxer for Jennifer Derby
Page 3 of 9
Case: acute renal failure
A 23 y.o. woman with no history of chronic illness is referred to your
nephrology clinic. Last month she had a high fever for 3 days, but had been
feeling better until 5 days ago, when she noticed her urine was tea-colored.
Subsequent urinations have been infrequent and darker brown, and her ankles
have become swollen, prompting a visit to her F.P. Physical exam is
remarkable for periorbital edema and 4+ edema of the lower extremities.
Plasma chemistries reveal creatinine of 3.5 mg/dl (normal 0.6-1.4 mg/dl) and
BUN (blood urea nitrogen) of 70 mg/dl (normal 11-23 mg/dl).
Why are BUN and creatinine elevated in this patient? Because her renal
function is down; there’s a drop in GFR.
Why has she developed edema? Due to the drop in GFR, the kidneys are not
excreting a certain amount of water. So, she’s retaining too much water, and
it’s causing an expansion of the extracellular fluid. This is common in post
streptococcyl glomelular nephritis. The strep infection damaged her glomelular
capillaries and filtration membrane. So, she has also begun to have hematuria—
blood in the urine.
Glomerular Filtration
 Unique structure and properties of glomerular membrane. It is very permeable
to water allowing lots of plasma to be filtered in a short time.
 Filterability of plasma constituents—small molecules freely filtered; large
molecules remain in blood vessels
 Physical forces (Starling forces, like colloid osmotic pressure) that determine
 Physiological mechanisms for modifying GFR
 Autoregulation of renal blood flow and GFR to maintain them at fairly constant
 Pathophysiology of proteinuria (protein in the urine)
 Glomerular filtration: first step in urine formation
 Plasma is filtered, due to high hydrostatic pressure, from glomerular capillaries
into Bowman’s capsule
 Normally, glomerular filtrate is essentially free of blood cells, proteins. Only a
small amount of protein is found in the filtrate unless there’s pathology.
 Glomerular filtrate, which initially resembles plasma, is heavily modified as it
passes down the nephron segments.
 Urine is very different from glomerular filtrate (plasma)
Glomerular membrane:
A. A molecular sieve—a screen
 Allows free passage of small stuff: water, small solutes (glucose, amino
acids, electrolytes): concentrations are the same on both sides of membrane
Renal #9
Tues, 03/18/03, 11am
Dr. Mallet
Jennifer Uxer for Jennifer Derby
Page 4 of 9
in the plasma and in the glomerular filtrate. So concentration of glucose in
Bowman’s capsule should be exactly the same as the concentration of
glucose in the plasma.
Passage of large molecules (proteins) and formed elements is impeded.
Their size and charge prevents large molecules from passing through. Only
very small amounts of protein are filtered into Bowman’s capsule. Most
are reabsorbed by endocytosis in the proximal tubule.
Large amounts of protein in urine (proteinuria) indicate renal injury
Molecular weight and charge affect filterability
[substance] in Bowman’s
Capsule/[substance] in plasma
--1 = freely filterable and
there’s the same concentration
on both sides of the membrane.
--Smaller the number means
that less substance crosses the
B. Structure of glomerular membrane
 The behavior of the membrane reflects its structure.
 Three distinct layers:
1. Fenestrated (Swiss cheese) capillary endothelium: highly permeable to
water, dissolved solutes
2. Glomerular basement membrane contains collagen, glycoproteins that
contain anionic charges—negative charges. These negative charges
repel other negatively charged molecules.
3. Podocyte epithelium: slit pores between podocytes restrict large
 In an electron micrograph of glomerular filtration membrane (B&L Fig. 406, p. 682) the podocyte epithelium, basement membrane, endothelial
fenestrae and slit pores can been seen. A slit diaphragm can be found
between the slit pores. This diaphragm is a lattice layer of protein (think
French windows). These small holes restrict the protein movement.
 So, proteins and large molecules are prevented from crossing the membrane
by 2 methods: 1. sterically—the size of the molecule that crosses the slit
diaphragm is limited and 2. electrostatically—negative molecules are
repelled. Glomelular capillaries are a clinched fist that’s been pressed into a
water balloon—Bowman’s capsule.
 Impact of electrostatic charge on filterability of large molecules (B&L Fig
40-15, p.690). Dextrans are large, artificial compounds about the size of
Renal #9
Tues, 03/18/03, 11am
Dr. Mallet
Jennifer Uxer for Jennifer Derby
Page 5 of 9
small ions
Ions with a positive charge are more
filtered than those that are neutral or
negatively charged.
Larger ions
Ions with a negative charge are least
filterable. Most proteins at physiologic
pH are polyanionic (negatively charged).
IV. Factors affecting glomerular filtration
A. Physical forces
 GFR is remarkably high (c. 125 ml/min, 180 L/day). This shows the high
water permeability in the kidney versus in other capillary beds.
 GFR is product of 3 physical factors:
1. Hydraulic permeability of glomerular membrane. If water is allowed
through, other dissolved molecules are also allowed through.
2. Total surface area for filtration (c. 2 m2) –LARGE!!!
– Product of 1 and 2 is ultrafiltration coefficient Kf (a.k.a. CFC: see Berne
& Levy, page 252
3. Capillary ultrafiltration pressure (UP—you pee, I pee, we all pee): high
hydrostatic pressure because its upstream from the capillary. This
provides the driving force for filtration.
B. Ultrafiltration pressure: driving force for glomerular filtration
 Reflects the balance of forces favoring filtration and absorption—
hydrostatic and colloid osmotic pressures.
 UP is determined by hydrostatic and colloid osmotic pressures in glomerular
capillaries, Bowman’s capsule:
 UP = (PGC + πBC) - (PBC + πGC) In words: UP is the (hydrostatic
pressure in the glomerular capillary + colloid osmotic pressure in Bowman’s
capsule) – (hydrostatic pressure in Bowman’s capsule + colloid osmotic
pressure in the glomerular capillary)
 Proteins draw fluid towards them—an osmotic effect.
 Because there’s no protein in Bowman’s Capsule:
πBC ~ 0, so UP = PGC - (PBC + πGC)
 UP is determined by balance of 3 pressures which favor filtration.
C. Skeletal muscle capillary
 At the arteriole end, capillary hydrostatic pressure > capillary colloid
osmotic pressure, so there’s net filtration, fluid flows out.
Renal #9
Tues, 03/18/03, 11am
Dr. Mallet
Jennifer Uxer for Jennifer Derby
Page 6 of 9
At the venous end, capillary colloid osmotic pressure > capillary hydrostatic
pressure, so fluid is net reabsorbed. There is a point where the 2 pressures
are equal.
 Overall in capillary beds other than those in the kidney, the forces favoring
filtration balance those opposing it. There’s only slightly more filtration
than absorption—about 2 – 4L/day due to lymph flow.
D. Glomerular capillary
 The pressure in the glomerular capillary is very high—about 55mmHg.
This is much higher than the pressures in a skeletal muscle capillary. It has
a high hydrostatic pressure because it’s upstream from a resistance vessel,
the efferent capillary.
 Glomerular capillaries have a fairly wide diameter and are arranged in
parallel, so the overall resistance is low. (Think resistors in parallel: the
total resistance is less than any of the individual resistances. 1/Rtot = 1/R1 +
1/R2 + …)
 As fluid flows from the afferent arteriole end to the efferent arteriolar end,
there’s net filtration. This is because of the increase in [proteins] shown by
the increase in the colloid osmotic pressure. During filtration, plasma
proteins are left behind and are more concentrated as more water is filtered
out. There is a net force for the filtration along the length of the capillary.
E. Physiological mechanisms for altering GFR
 GFR = Kf * UP
 Capillary filtration coefficient: K f = (surface area available for filtration) *
(hydraulic permeability).
 Altered Kf: mesangial cell contraction lowers Kf
 Altered UP: changes in PGC
 PGC determined by 3 factors:
– Renal arterial blood pressure
– Afferent arteriolar resistance
– Efferent arteriolar resistance
 Glomerular mesangial cells can alter Kf loops.
 Contraction of mesangial cells shortens capillary loops where they are
found, lowers Kf and, thus, lowers GFR. When K f is lowered, there’s
less surface area for filtration.
 Angiotensin II promotes the mesangial cells contractraction—this lowers
GFR. Other effects of angiotensin II increase GFR. They have a
contractile protein and function a lot like smooth muscle.
GFR is physiologically controlled by adjusting resistance of afferent
and efferent arterioles
 Afferent arteriolar constriction:
– Greater pressure drop upstream of glomelular capillaries
– PGC falls, which lowers GFR
Renal #9
Tues, 03/18/03, 11am
Dr. Mallet
Jennifer Uxer for Jennifer Derby
Page 7 of 9
–  resistance to flow → ↓ pressure in the capillary → ↓ GFR
– Renal blood flow falls ( resistance)
Efferent arteriolar constriction:
– Downstream from glomerular capillaries
– Pooling of blood in glomerular capillaries
– Increased PGC increases GFR
– Angiotensin II causes this effect.
– What would happen to renal blood flow? It decreases because of the
increase in resistance.
– Here, GFR can increase while renal blood flow decreases.
F. Things affecting pressure in the glomelular capillary
 PGC is affected by
1. systemic arterial pressure (PA)—there’s a change in glomerular
hydrostatic pressure and a change in the rate of filtration,
2. afferent arteriolar resistance (RA) — ↓ P, ↓ GFR, ↓ blood flow
3. efferent arteriolar resistance (RE) —  P,  GFR, ↓ blood flow
The pressure in the peritubular capillaries is then lowered. This provides
more time for filtration
 The ‘garden hose’ analogy—think of the afferent arteriole, glomelular
capillary, Bowman’s capsule, the efferent arteriole as a garden hose.
There’s a hole in this hose—that’s equal to the glomeluar capillary with
water filtration into Bowman’s capsule.
 Scenario 1: Increased systemic arterial pressure
 water into the hose =  systemic arterial pressure.
 water spraying out of the hole in the hose =  GFR due to the 
systemic arterial pressure.
 water out of the end of the hose =  renal blood flow.
Note that auto-regulation minimizes these changes in GFR and renal
blood flow due to a change in systemic arterial pressure.
 Scenario 2: Afferent arteriolar constriction
The hose is constricted proximal to the hole in it. So, there’s very little
water out of the hole and out of the end of the hose. This is ↓ in GFR
and ↓ in renal blood flow.
 Scenario 3: Moderate efferent arteriolar constriction
The hose is constricted distally to the hole. Now, there’s  water
spraying from the hole =  GFR, but there’s ↓ water pouring out of the
end of the hose = ↓ renal blood flow.
G. Hydrostatic pressures in renal microcirculation: effects of arteriolar constriction
 See the power points for the graph.
 Don’t memorize the values. Know changes  or ↓.
 Normal: afferent arterioles present some resistance, so the pressure will fall.
The pressure is high in the glomelular capillary beds. There’s a further drop
Renal #9
Tues, 03/18/03, 11am
Dr. Mallet
Jennifer Uxer for Jennifer Derby
Page 8 of 9
in the efferent capillaries, and the hydrostatic pressure is low in the
peritubular capillaries.
 Afferent constriction: greater pressure ↓ upstream of the glomelular
capillaries, ↓ GFR, ↓ peritubular pressure
 Efferent constriction:  pressure because the pressure drop is downstream
of the glomelular capillaries,  glomelular filtration, ↓ peritubular pressure
 Autoregulation of renal blood flow and GFR
(The graphs shown in the ppts are more accurate than in Fig. 40-18, p. 693)
 Rates are fairly constant in large pressure changes of mean arterial blood
pressure from 80 – 180 mmHg.
A. Mechanisms for auto-regulating renal blood flow and GFR
1. Myogenic response to increased systemic arterial pressure
 Myo = muscle—muscle constrictions primarily regulate renal blood
flow. GFR is regulated as a result of this.
 Systemic arterial pressure   stretches blood vessels: cortical radial
arteries & afferent arterioles  it constricts in response   resistance
  renal blood flow   pressure   stretch  relaxation.
 Increased vascular resistance   renal blood flow
 PGC  
 
 The opposite occurs if systemic arterial blood pressure falls.
2. Tubuloglomerular feedback responses to:
– Increased GFR
– Decreased GFR
– This a is communication between the nephron tubule and the glomeluar
circulation. This is mediated by the juxtaglomerular (JG) apparatus.
B. Autoregulatory mechanisms involving juxtaglomerular apparatus
 Located at beginning of distal convoluted tubule. Cells of the JG apparatus
lie near the glomerulus.
 Components found at the beginning of the distal convoluted tubule:
– Macula densa: in wall of distal convoluted tubule. It is a dense patch of
cells that monitor rate of fluid flow through the distal convoluted tubule
and signal to the adjacent arterial cells to constrict or relax.
– Extraglomerular mesangial cells—mediators between the macula densa
and the granular cells, and help transfer the signal.
– Juxtaglomerular (granular) cells in afferent & efferent arteriole smooth
muscle. Granular cells contain renein.
 Juxtaglomerular apparatus responds to blood pressure changes to maintain
GFR nearly constant.
C. TGF response to increased renal blood pressure
 Initially, there’s an increase in GFR because of the increased hydrostatic
pressure in the glomelular capillaries.
Renal #9
Tues, 03/18/03, 11am
Dr. Mallet
Jennifer Uxer for Jennifer Derby
Page 9 of 9
More fluid filtered into the nephrons and flows thru. This is sensed by the
macula densa.
 The macula densa signals cells in the adjacent arteriole cells to constrict.
The signaling is done using adenosine.
 There’s now afferent arteriole constriction causing a decrease in flow and a
decrease in GFR.
 See power points for the entire flow chart.
D. Response to decreased renal blood pressure
 GFR falls; less Na+, Cl- filtered and less delivered to macula densa, which
senses this drop in fluid delivery
 Macula densa signals granular cells to secrete renin, which catalyzes the
production of angiotensin II.
 Increased circulating angiotensin II:
– Potent vasoconstrictor  restores blood pressure
– Efferent arteriolar vasoconstriction in the kidney which restores GFR
– The afferent arteriole is not as sensitive to angiotensin II, so it doesn’t
constrict as much.
– Why do we want to continue filtering? To eliminate waste products.
– Maintenance of GFR when systemic arterial pressure has fallen it allows
removal of waste while the constriction of the efferent arteriole diverts
renal blood to the rest of the body and stabilize blood pressure.
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