2. ā¢ Mental integrity is a sine qua non of the free and independent
life. As intermittent rays of light blend into moving images on
the cinematographic screen, so the multiform activities within
the brain are integrated into images of consciousness and
brought into an unstable focus to form that fleeting entity
which we call personality, or self.
ā¢ But let the composition of our internal environment suffer change,
let our kidneys fail for even a short time to fulfill their task, and
our mental integrity, our personality, is destroyed.
ā¢ HOMER WILLIAM SMITH
3. HOMER WILLIAM SMITH
ā¢ Renal clearance methods,
ā¢ Non-invasive methods for the
measurement of glomerular
filtration rate, of renal blood
flow
ā¢ Tubular transport capacity,
and provided novel insights
into the mechanisms of
excretion of water and
electrolytes
January 2,1895-March 25,1962
4. GENERAL PRINCIPLES
ā¢ Solute movement across the
membrane occurs by
1. Active transport
2. Passive transport
3. Endocytosis
ā¢ Diffusion of water occurs
1. Water channels
6. Transcelluar Pathway and Paracellualr pathway
ā¢ Paracellular transport refers to the transfer of substances across an
epithelium by passing through the intercellular space between the
cells.
ā¢ Transcellular transport, where the substances travel through the cell,
passing through both the apical membrane and basolateral
membrane
8. PROXIMAL TUBULES
ā¢ Reabsorbs 67% of the filtered water, Na+ , K+ , Cl- and other
solutes.
ā¢ Also absorbs glucose and amino acids.
ā¢ Key element in the proximal tubule absorption is Na+ K+
ATPase in the basolateral membrane.
9. Na+ absorption
ā¢ Na+ is absorbed by different mechanisms in first and second half of
the proximal tubules.
ā¢ In the first half
ā¢ Na+ is reabsorbed along with HCO3 and number of other solutes
ā¢ Na+ uptake into the cell is couples with either H+ or organic solutes
10.
11.
12. ā¢ Second half of the proximal tubule
ā¢ Na+ is reabsorbed along with Cl-
13. Absorption of Water
ā¢ 67%
ā¢ Trans tubular osmotic
gradient is the driving force
ā¢ PT is highly permeable to
water
ā¢ Osmosis
ā¢ Aquaporin's
ā¢ OBLIGATORY WATER
TRANSPORT
14. Absorption of proteins
ā¢ Proteins filtered across the glomerulus are reabsorbed in
the proximal tubule.
ā¢ Peptide hormones, small proteins, and small amounts of
large proteins such as albumin are filtered by the
glomerulus.
15.
16. ā¢ It is normal to find trace amounts of protein in the urine.
ā¢ Trace amounts of protein in the urine can be derived from two
sources:
(1) filtration and incomplete reabsorption by the proximal tubule and
(2) synthesis by the thick ascending limb of the loop of Henle.
ā¢ Cells in the thick ascending limb produce Tamm-Horsfall glycoprotein
and secrete it into the tubular fluid.
ā¢ However, more than trace amounts of protein in the urine is
indicative of renal disease.
17. Transport across Henleās Loop
ā¢ Reabsorbs 25% of the filtered Nacl
ā¢ Reabsorbs 15% of the water
ā¢ Reabsorption of NaCl in the loop of Henle occurs in
both thin and thick limbs of ascending limb
ā¢ Thin descending limb is not permeable to Nacl
18. ā¢ Water reabsorption occurs in descending limb through
aquaporin channels
ā¢ Ascending limb is impermeable to water
ā¢ Ca+2 and HCO3- are also absorbed
19.
20.
21. Transport across Distal tubules and Colleting
Duct
ā¢ 8% of the filtered Nacl reabsorbed
ā¢ 8%-17% of the Water reabsorbed
ā¢ Secrete variable amount of K+ and H+
22.
23. Transport across the collecting duct
ā¢ The collecting tubule consists of 2 types of cells
1. Principle cell
2. Intercalated cell
ā¢ Principle cell reabsorbs NaCl and H2O
ā¢ Secretes K+
ā¢ Intercalated cell secretes either H+ or HCO3-
ā¢ Important in regulating acid base balance
29. Urea transport
ā¢ The kidney filters, reabsorbs, and secretes urea
ā¢ The liver generates urea from NH+4, the primary nitrogenous end
product of amino acid catabolism.
ā¢ The primary route for urea excretion is the urine, although some urea
exits the body through the stool and sweat.
30. ā¢ The kidney freely filters urea at the glomerulus, and then it both
reabsorbs and secretes it.
ā¢ Because the tubules reabsorb more urea than they secrete, the
amount of urea excreted in the urine is less than the quantity filtered
ā¢ The primary sites for urea reabsorption are the proximal tubule and
the medullary collecting duct,
ā¢ The primary sites for secretion are the thin limbs of the loop of Henle.
31.
32. ā¢ Urea transport depends primarily on urea concentration differences
across the tubule epithelium,
ā¢ Changes in urine flow unavoidably affect renal urea handling
ā¢ At low urine flow, when the tubule reabsorbs considerable water and
therefore much urea, the kidneys excrete only ~15% of filtered urea
ā¢ The kidneys may excrete as much as 70% of filtered urea at high urine
flow, when the tubules reabsorb relatively less water and urea
33. Glucose transport
ā¢ The fasting plasma glucose concentration
70 to 100 mg/dL and is regulated by insulin
and other hormones.
ā¢ The kidneys freely filter glucose at the
glomerulus and then reabsorb it, so that
only trace amounts normally appear in the
urine
34. ā¢ The proximal tubule reabsorbs nearly all the
filtered load of glucose,
ā¢ In the proximal tubule, luminal [glucose] is
initially equal to plasma [glucose].
ā¢ As the early proximal tubule reabsorbs
glucose, luminal [glucose] drops sharply,
falling to levels far lower than those in the
interstitium.
ā¢ Accordingly, glucose reabsorption occurs against a concentration gradient
and must therefore be active.
35.
36. Glucose excretion in the urine occurs only when
the plasma concentration exceeds a threshold
The glucose titration curve is
obtained experimentally by infusing
glucose and measuring its rate of
reabsorption as the plasma
concentration is increased
37. ā¢Filtered load.
ā¢Glucose is freely filtered across glomerular capillaries, and the
filtered load is the product of GFR and plasma glucose concentration
ā¢
ā¢ filtered load = GFR Ć [P]x
ā¢
ā¢Thus, as the plasma glucose
concentration is increased, the filtered
load increases linearly.
38. ā¢Reabsorption.
ā¢At plasma glucose concentrations less than 200 mg/dL, all of the
filtered glucose can be reabsorbed because Na+-glucose
cotransporters are plentiful.
ā¢In this range, the curve for reabsorption is
identical to that for filtration; that is,
reabsorption equals filtration.
ā¢The number of carriers is limited
40. ā¢Excretion.
ā¢Below plasma glucose concentrations of 200 mg/dL, all of the
filtered glucose is reabsorbed, and none is excreted.
ā¢At plasma glucose concentrations
above 200 mg/dL, the carriers are
nearing the saturation point.
ā¢Most of the filtered glucose is
reabsorbed, but some is not; the
glucose that is not reabsorbed is
excreted
41. ā¢The plasma concentration at which glucose is first excreted in
the urine is called threshold, which occurs at a lower plasma
concentration than does Tm.
ā¢Above 350 mg/dL, Tm is reached and the carriers are fully
saturated.
ā¢The curve for excretion now increases linearly as a function of
plasma glucose concentration, paralleling that for filtration
42. ā¢ The Tm for glucose is approached gradually, rather than
sharply , a phenomenon called splay.
ā¢ Splay is that portion of the titration curve where reabsorption is
approaching saturation, but it is not fully saturated.
ā¢ Because of splay, glucose is excreted in the urine (i.e., at
threshold) before reabsorption levels off at the Tm value
43. ā¢ Low affinity of the Na+-glucose cotransporter
ā¢ Tm for the whole kidney reflects the average Tm of all
nephrons,
ā¢ All nephrons do not have exactly the same Tm.
ā¢ Some nephrons will reach Tm at lower plasma concentration
than others, and glucose will be excreted in the urine before
the average Tm is reached
45. ā¢ Diuretics, as the name implies, are drugs that cause an increase in
urine output
ā¢ All diuretics have as their common mode of action the primary
inhibition of Na+ reabsorption by the nephron.
ā¢ Consequently, they cause an increase in the excretion of Na+, termed
natriuresis
Editor's Notes
Solutes can be transported across the membrane by active, passive transport and by endocytosis.
Solute movement occurs by both active and passive transport mechanism whereas water transport is passive.
Passive transport is from an area of higher concentration to lower concentration.
Diffusion of water occurs through channels in the cell membrane and is driven by osmotic pressure gradient
Filtered load (FĀ°) is calculated by multiplying the
GFR with plasma concentration of the substance (Px),
The excretion rate (EĀ°) can be
calculated by multiplying urine flow rate (V) and the
urinary concentration of the substance (Ux).
Persons with central diabetes insipidus
have a urine-concentrating defect that can be corrected
by the administration of exogenous AVP.
In A, we assume a normal urine flow and thus a urea
excretion of 40% of the filtered load. The numbered yellow boxes indicate the fraction of the filtered load that
various nephron segments reabsorb. The tALH and the tip of the tDLH in juxtamedullary nephrons secrete
urea. In superficial nephrons, the entire tDLH may secrete urea. The red box indicates the fraction of the
filtered load jointly secreted by both nephron types. The green boxes indicate the fraction of the filtered load
that remains in the lumen. The values in the boxes are approximations. UT-A1, UT-A2, and UT-A3 are urea
transporters.
In the very early proximal tubule (Fig. 36-1B), [urea] in the lumen is the same
as in blood plasma. However, paracellular fluid reabsorption along the proximal
tubule sweeps some urea along with it through solvent drag (see Chapter 20). In
addition, water reabsorption tends to increase [urea] in the lumen, thereby
generating a favorable transepithelial gradient that drives urea reabsorption by
diffusion through the transcellular or paracellular pathway. The greater the fluid
reabsorption along the proximal tubule, the greater is the reabsorption of urea
through both solvent drag and diffusion.
In juxtamedullary nephrons, as the tubule fluid in the thin descending limb
(tDLH) approaches the tip of the loop of Henle, [urea] is higher in the medullary
interstitium than in the lumen (see Chapter 38). Thus, the deepest portion of the
tDLH secretes urea through facilitated diffusion (Fig. 36-1C) mediated by the urea
transporter UT-A2, which is encoded by the SLC14A2 gene. As the fluid turns the
corner to flow up the thin ascending limb (tALH), the tubule cells continue to
secrete urea into the lumen, probably also by facilitated diffusion
The tDLH of superficial nephrons is located in the inner stripe of the outer
medulla. Here, the interstitial [urea] is higher than the luminal [urea] because the
vasa recta carry urea from the inner medulla. Because the tDLH cells of these
superficial nephrons appear to have UT-A2 along their entire length, these cells
secrete urea. Thus, both superficial and probably also juxtamedullary nephrons
contribute to urea secretion, raising urea delivery to ~110% of the filtered load at
the level of the cortical collecting ducts.
Finally, the inner medullary collecting duct (IMCD) reabsorbs urea by a
transcellular route that is unusual in that both the apical and basolateral steps occur
by facilitated diffusion (Fig. 36-1E). The UT-A1 urea transporter moves urea
across the apical membrane of the IMCD cell, whereas UT-A3 probably mediates
urea movement across the basolateral membrane. Arginine vasopressin (AVP)ā
also known as antidiuretic hormone (ADH)āstimulates UT-A1 but not UT-A3. In
Chapter 38, we discuss the role of urea transport in the urinary concentrating
mechanism.
Because urea transport depends primarily on urea concentration differences across
the tubule epithelium, changes in urine flow unavoidably affect renal urea handling
(Fig. 36-2). At low urine flow, when the tubule reabsorbs considerable water and
therefore much urea, the kidneys excrete only ~15% of filtered urea (see Fig. 38-
6). However, the kidneys may excrete as much as 70% of filtered urea at high urine
flow, when the tubules reabsorb relatively less water and urea. During the
progression of renal disease, the decline of the glomerular filtration rate (GFR)
leads to a low urine flow and urea retention, and thus an increase in BUN.
To understand the curve for excretion, compare those for filtration and reabsorption