Physiology of Kidney Functions and Nephron Structure

Physiology of Kidney
Gilbert S 2014
BASICS OF KIDNEY
Functions of Kidney
• Maintaining water balance
• Maintaining proper osmolarity (through water balance
mainly)
• Regulating quantity and concentration of most ECF ions
• Maintaining proper plasma volume
• Maintain acid-base balance
• Excrete waste metabolism
• Excrete many foreign compounds
• Produce EPO
• Produce renin
• Convert vitamin D to its active form
Nephron
• Nephron is the functional unit of the kidney
• Two distinct regions – cortex and medulla
(made up of striated triangles  renal
pyramids)
• Each nephron consists of a vascular
component and a tubular component
Vascular Component of the Nephron
• Glomerulus is made up of
afferent arteriole and
efferent arteriole
• No oxygen or nutrients are
extracted for kidney use in
the glomerulus
• Efferent arteriole 
subdivides into peritubular
capillaries  supply renal
tissue & involved in
exchange between the
tubular system and blood
during conversion of filtered
fluid into urine
Tubular Component of the Nephron
• The nephron’s tubular component is a hollow,
fluid-filled tube formed by a single layer of
epithelial cells.
• The tubular component begins with Bowman’s
capsule
• There it goes to proximal tubule  loop of
Henle (descending and ascending) 
Juxtaglomerular apparatus  distal tubule 
collecting tubule
Two Types of Nephrons
Cortical Nephrons Juxtamedullary Nephrons
• Outer layer of cortex • Inner layer of cortex
• Hairpin loop dips only slightly • Loop plunges through the
into the medulla
entire depth of medulla
• Peritubular capillaries do not
form vasa recta but instead • Peritubular capillaries form
entwine around these hairpin vascular loops
nephrons’ short loops of Henle known as vasa recta
in the same manner as the
peritubular capillaries wrap (“straight vessels”), which
around the proximal and distal run in close association with
tubules in both types of the long loops of Henle
nephrons.
• 20%
• 80%
Three Basic Renal Processes
• Glomerular Filtration
• Tubular Reabsorption
• Tubular Secretion
Glomerular Filtration
• ~20% of plasma is
filtered
• First step of urine
formation
• 125 mL of glomerular
filtrate are formed
collectively each minute
Tubular Reabsorption
• As filtrate flows through
the tubule, substances
of value to the body are
returned to the
peritubular capillary
plasma
• Reabsorbed substance
 carried by
peritubular capillaries
 venous system 
back to the heart
Tubular Secretion
• Selective transfer of
substances from the
peritubular capillary
blood into the tubular
lumen
• 2nd route for substances
to enter the renal
tubules from the blood
GLOMERULAR FILTRATION
Composition of Glomerular Membrane
• Glomerular Capillary Wall
• Basement Membrane
• Inner layer of Bowman’s capsule
Glomerular Membrane
Collectively, these layers function as a fine
molecular sieve that retains the blood cells and
plasma proteins but permits H2O and solutes of
small molecular dimension to filter through
Glomerular Membrane
• Glomerular capillary wall consists of a single
layer of flattened endothelial cells.
• It is perforated by many large pores that make
it more than 100 times more permeable to
H2O and solutes than capillaries elsewhere in
the body
Glomerular Membrane
• Basement membrane is an acellular gelatinous layer
composed of collagen and glycoproteins that is
sandwiched between the glomerulus and Bowman’s
capsule.
• The collagen provides structural strength, and the
glycoproteins discourage the filtration of small plasma
proteins.
• The larger plasma proteins cannot be filtered because
they cannot fit through the capillary pores, but the
pores are just barely large enough to permit passage of
albumin, the smallest of plasma proteins.
Glomerular Membrane
• However, because the glycoproteins are negatively
charged, they repel albumin and other plasma
proteins, which are also negatively charged.
• Therefore, plasma proteins are almost completely
excluded from the filtrate, with less than 1% of the
albumin molecules escaping into Bowman’s capsule.
• The small proteins that do slip into the filtrate are
picked up by the proximal tubule by endocytosis, then
degraded into constituent amino acids that are
returned to the blood. Thus, urine is normally protein
free.
Glomerular Membrane
• The final layer of the glomerular membrane is the inner
layer of Bowman’s capsule.
• It consists of podocytes, octopus-like cells that encircle
the glomerular tuft.
• Each podocyte bears many elongated foot processes
that interdigitate with foot processes of adjacent
podocytes
• The narrow slits between adjacent foot processes,
known as filtration slits, provide a pathway through
which fluid leaving the glomerular capillaries can enter
the lumen of Bowman’s capsule.
• Glomerular capillary BP is the major force that
causes glomerular filtration
• No local energy is used to move fluid from the
plasma across the glomerular membrane into
Bowman’s capsule
• The glomerular capillaries are more permeable
than capillaries elsewhere, so more fluid is
filtered for a given filtration pressure
• The balance of forces across the glomerular
membrane is such that filtration occurs the entire
length of the capillaries
Three forces are involved:
1. Glomerular capillary blood pressure
2. Plasma-colloid osmotic pressure
3. Bowman’s capsule hydrostatic pressure
Glomerular Capillary Blood Pressure
• Hydrostatic pressure
exerted by the blood
within glomerulus
• Depends on:
1. Contraction of heart
2. Resistance to blood
flow by afferent &
efferent arteriole
• 55 mmHg  favours
filtration (major force)
Plasma-Colloid Osmotic Pressure
• Caused by unequal
distribution of plasma
proteins across the
glomerular membrane
• Resulting in H2O to
move by osmosis from
Bowman’s capsule into
the glomerulus
• 30 mmHg  opposes
filtration
Bowman’s Capsule Hydrostatic
Pressure
• Pressure exerted by the
fluid in this initial part
of the tubule
• 15 mmHg – Opposes
filtration
Glomerular Filtration Rate
• Net difference favoring
filtration (10 mmHg) is the net
filtration pressure
• Actual rate of filtration,
glomerular filtration rate (GFR)
• GFR depends on:
1. Net filtration pressure
2. Glomerular surface area
available for penetration
3. How permeable the
glomerular membrane is
• GFR in male  125 mL/min
• GFR in female  115 mL/min
Regulation of GFR
• Glomerular capillary blood pressure can be
controlled to adjust the GFR to suit the body’s
needs.
• Two major mechanisms:
1. Autoregulation (aimed at preventing
spontaneous changes in GFR)
2. Extrinsic sympathetic control (aimed at long-
term regulation of arterial BP)
Autoregulation
• Inadvertent changes in GFR
are largely prevented by
intrinsic regulatory
mechanisms initiated by the
kidneys themselves 
autoregulation
• The kidneys can, within limits,
maintain a constant blood flow
into the glomerular capillaries
despite changes in the driving
arterial pressure
• They do so primarily by
altering afferent arteriolar
caliber, thereby adjusting
resistance to flow through
these vessels.
Autoregulation
Two intrarenal mechanisms contribute to
autoregulation:
1. Myogenic mechanisms  responds to
changes in pressure within the nephron’s
vascular component
2. Tubuloglomerular feedback  senses
changes in the salt level in the fluid flowing
through the nephron’s tubular compartment
Myogenic Mechanism
• Arteriolar vascular
smooth muscle contracts
inherently in response to
the stretch accompanying
increased pressure within
the vessel
• Accordingly, the afferent
arteriole automatically
constricts on its own
when it is stretched
because of an increased
arterial driving pressure.
Tubuloglomerular Feedback (TGF)
• Involves the
juxtaglomerular apparatus
• The smooth muscle cells
within the wall of the
afferent arteriole in this
region are specialized to
form granular cells
• Specialized tubular cells in
this region are collectively
known as macula densa
detect changes in the salt
level of the fluid passing
through the tubule
GFR
• If the GFR is increased secondary to an elevation in
arterial pressure, more fluid than normal is filtered and
flows through the distal tubule.
• In response to the resultant rise in salt delivery to the
distal tubule, the macula densa cells release ATP and
adenosine, both of which act locally as a paracrine on
the adjacent afferent arteriole, causing it to constrict,
thus reducing glomerular blood flow and returning GFR
to normal
• Macula densa  secrete NO  puts the brakes on the
action of ATP and adenosine at afferent arteriole
Importance of GFR
• The myogenic and tubuloglomerular feedback
mechanisms work in unison to autoregulate
the GFR within the mean arterial blood
pressure range of 80 to 180 mm Hg
• Autoregulation is important because
unintentional shifts in GFR could lead to
dangerous imbalances of fluid, electrolytes,
and wastes
Importance of Extrinsic Sympathetic
Control of GFR
• GFR can be changed on purpose – even when
MAP is within autoregulatory range – by extrinsic
control mechanisms that override the
autoregulatory responses
• Extrinsic control of GFR, which is mediated by
sympathetic nervous system input to the afferent
arterioles, is aimed at long-term regulation of
arterial blood pressure.
• The parasympathetic nervous system does not
exert any influence on the kidneys.
Baroreceptor Reflex in Extrinsic
Control of GFR
• Baroreceptor reflex  decrease GFR in
response to a fall in BP
• Vasoconstriction as a compensatory
mechanism to increase TPR
• Afferent arterioles have α1-adrenergic
receptors and are innervated with
sympathetic vasoconstrictor fibers to a far
greater extent than the efferent arterioles are
Baroreceptor Reflex in Extrinsic
Control of GFR
• Other mechanisms, such as increased tubular
reabsorption of H2O and salt, and increased
thirst, also contribute to long-term maintenance
of blood pressure, despite a loss of plasma
volume, by helping restore plasma volume.
• A hormonally adjusted reduction in the tubular
reabsorption of H2O and salt also contributes to
the increase in urine volume.
• The two renal mechanisms—increased
glomerular filtration and decreased tubular
reabsorption of H2O and salt
Filtration Coefficient (Kf)
• The rate of glomerular filtration depends on
the filtration coefficient (Kf) as well as on the
net filtration pressure.
• Both factors on which Kf depends—the
surface area and the permeability of the
glomerular membrane— can be modified by
contractile activity within the membrane
• The surface area available
for filtration within the
glomerulus is represented
by the inner surface of
the glomerular capillaries
that comes into contact
with blood.
• Each tuft of glomerular
capillaries is held ogether
by mesangial cells
• These cells contain
contractile elements (that
is, actin-like filaments).
• Contraction of these
mesangial cells closes off
a portion of the filtering
capillaries, reducing the
surface area available for
filtration within the
glomerular tuft.
• When the net filtration
pressure remains
unchanged, this reduction
in Kf decreases the GFR.
• Sympathetic stimulation
causes the mesangial cells
to contract, thus providing a
second mechanism (besides
promoting afferent
arteriolar vasoconstriction)
by which sympathetic
activity can decrease the
GFR.
• Podocytes also possess
actin-like contractile
filaments, whose
contraction or relaxation
can, respectively,
decrease or increase the
number of filtration slits
open in the inner
membrane of Bowman’s
capsule by changing the
shapes and proximities of
the foot processes
TUBULAR REABSORPTION
• Tubular reabsorption is a highly selective process
• In most cases, the quantity reabsorbed of each
substance is the amount required to maintain the
proper composition and volume of the internal
fluid environment.
• In general, the tubules have a high reabsorptive
capacity for substances needed by the body and
little or no reabsorptive capacity for substances
of no value
• Only excess amounts of essential materials such
as electrolytes are excreted in the urine
• As H2O and other
valuable constituents are
reabsorbed, the waste
products remaining in the
tubular fluid become
highly concentrated
• The tubules typically
reabsorb 99% of the
filtered water, 100% of
the filtered sugar, and
99.5% of the filtered salt
• Throughout its length, the tubule wall is one cell
thick and is close to a surrounding peritubular
capillary
• Adjacent tubular cells do not come into contact
with each other except where they are joined by
tight junctions at their lateral edges near their
luminal membranes, which face the tubular
lumen.
• The interstitial fluid lies in the gaps between
adjacent cells – the lateral spaces
• The basolateral membrane faces the
interstitial fluid at the base and lateral edges
of the cell.
• The tight junctions largely prevent substances
from moving between the cells, so materials
must pass through the cells to leave the
tubular lumen and gain entry to the blood
Transepithelial Transport
• To be reabsorbed, a substance
must go across five distinct
barriers:
1. It must leave the tubular fluid
by crossing the luminal
membrane of the tubular cell.
2. It must pass through the cytosol
from one side of the tubular cell
to the other
3. It must cross the basolateral
membrane of the tubular cell to
enter the interstitial fluid.
4. It must diffuse through the
interstitial fluid.
5. It must penetrate the capillary
wall to enter the blood plasma.
Reabsorption
Passive Active
• All steps in transepithelial • Requires energy in one of
transport are passive the steps, even if four of the
steps are passive
• Against electro-chemical
gradient
• Sodium, glucose, AA,
phosphate
Sodium Reabsorption
• Of the total energy
spent by the kidneys,
80% is used for Na+
transport
• 67% is reabsorbed in
the proximal tubule,
25% in the loop of
Henle, and 8% in the
distal and collecting
tubules
Sodium Reabsorption
• Sodium reabsorption in the proximal tubule plays a pivotal
role in reabsorbing glucose, amino acids, H2O, Cl-, and urea.
• Sodium reabsorption in the ascending limb of the loop of
Henle, along with Cl- reabsorption, plays a critical role in
the kidneys’ ability to produce urine of varying
concentrations and volumes, depending on the body’s need
to conserve or eliminate H2O.
• Sodium reabsorption in the distal and collecting tubules is
variable and subject to hormonal control. It plays a key role
in regulating ECF volume, which is important in long-term
control of arterial blood pressure, and is linked in part to K+
secretion.
Sodium Reabsorption
• Sodium is reabsorbed throughout the tubule with
the exception of the descending limb of the loop
of Henle
• Na+ reabsorption involves the energy-dependent
Na+–K+ ATPase carrier located in the tubular cell’s
basolateral membrane  moves sodium ion
against a concentration gradient
• a concentration gradient is established that favors
the passive movement of Na+ from its higher
concentration in the tubular lumen across the
luminal border into the tubular cell
Sodium Reabsorption
Movement of Na+ across the luminal membrane
is always a passive step except in collecting duct
where it crosses the luminal border through a
sodium leak channel
Sodium Reabsorption
• In the proximal tubule and loop of Henle, a
constant percentage of the filtered Na+ is
reabsorbed regardless of the Na+ load (the
total amount of Na+ in the body fluids).
• In the distal and collecting tubules, the
reabsorption of a small percentage of the
filtered Na+ is subject to hormonal control 
inversely related to the magnitude of sodium
load in the body
Sodium Reabsorption
• The Na+ load in the body is reflected by the
ECF volume.
• Sodium and its accompanying anion Cl-
account for more than 90% of the ECF’s
osmotic activity
Renin-Angiotensin-Aldosterone System
(RAAS)
• The granular cells of the juxtaglomerular
apparatus secrete an enzymatic hormone,
renin, into the blood in response to a fall in
NaCl, ECF volume, and arterial blood pressure
• This function is in addition to the role the
macula densa cells of the juxtaglomerular
apparatus play in autoregulation.
RAAS
Three inputs to granular cells that increase renin secretion:
1. The granular cells themselves function as intrarenal
baroreceptors. They are sensitive to pressure changes within the
afferent arteriole. When the granular cells detect a fall in blood
pressure, they secrete more renin.
2. The macula densa cells in the tubular portion of the
juxtaglomerular apparatus are sensitive to the NaCl moving past
them through the tubular lumen. In response to a fall in NaCl, the
macula densa cells trigger increased renin secretion.
3. The granular cells are innervated by the sympathetic nervous
system. When blood pressure falls below normal, the
baroreceptor reflex increases sympathetic activity. As part of this
reflex response, increased sympathetic activity stimulates the
granular cells to secrete more renin.
RAAS
• Two distinct types of tubular cells are located in
the distal and collecting tubules: principal cells
and intercalated cells.
• The more abundant principal cells are the site of
action of aldosterone and vasopressin and thus
are involved in Na+ reabsorption and K+ secretion
(both regulated by aldosterone) and in H2O
reabsorption (regulated by vasopressin).
• Intercalated cells, by contrast, are concerned with
acid–base balance.
RAAS
• Aldosterone increases Na+ reabsorption by the
principal cells of the distal and collecting tubules
• It promotes insertion of additional Na1 leak
channels into the luminal membranes and
additional Na+–K+ pumps into the basolateral
membranes of these cells
• The net result is greater passive movement of Na+
into these distal and collecting tubular cells from
the lumen and increased active pumping of Na+
out of the cells into the plasma
RAAS
• RAAS thus promotes salt retention and a
resulting H2O retention and rise in arterial
blood pressure
• Factors that trigger renin release:
1. Salt depletion
2. Plasma volume reduction
3. Decreased arterial blood pressure
RAAS
• Angiotensin II is a potent constrictor of the
systemic arterioles, directly increasing blood
pressure by increasing total peripheral resistance
• Furthermore, it stimulates thirst (increasing fluid
intake) and stimulates vasopressin (a hormone
that increases H2O retention by the kidneys),
both of which contribute to plasma volume
expansion and elevation of arterial pressure
Natriuretic Peptides
• RAAS is opposed by a Na+-losing, blood pressure–
lowering system that involves the hormones atrial
natriuretic peptide (ANP) and brain natriuretic peptide
(BNP)
• ANP is produced in the atrial cardiac muscle cells while
BNP is produced primarily in the ventricular cardiac
muscle cells
• ANP and BNP are stored in granules and released when
the heart muscle cells are mechanically stretched by an
expansion of the circulating plasma volume when the
ECF volume is increased.
• NPs promote natriuresis and accompanying
diuresis, decreasing the plasma volume, and
also directly influence the cardiovascular
system to lower the blood pressure
• The main action of ANP and BNP is to directly
inhibit Na+ reabsorption in the distal parts of
the nephron, thus increasing Na+ and
accompanying osmotic H2O excretion in the
urine.
• The NPs inhibit renin secretion by the kidneys and act
on the adrenal cortex to inhibit aldosterone secretion.
In addition, they inhibit the secretion and actions of
vasopressin
• ANP and BNP also promote natriuresis and
accompanying diuresis by increasing the GFR.
• They dilate the afferent arterioles and constrict the
efferent arterioles, thus raising glomerular capillary
blood pressure and increasing the GFR.
• They further increase the GFR by relaxing the
glomerular mesangial cells, leading to an increase in Kf
(Slides 39)
• ANP is more powerful in producing natriuresis
and diuresis than BNP is
• ANP and BNP directly lower blood pressure by
decreasing the cardiac output and reducing
peripheral vascular resistance by inhibiting
sympathetic nervous activity to the heart and
blood vessels
Glucose and Amino Acids
Reabsorption
• Reabsorption of glucose and amino acids
involves secondary active transport.
• With this process, specialized symport
carriers, such as the sodium and glucose
cotransporter (SGLT), located only in the
proximal tubule simultaneously transfer both
Na+ and the specific organic molecule from
the lumen into the cell
Active Reabsorption
• Because a limited number of each carrier type
is present in the tubular cells, there is an
upper limit on how much of a particular
substance can be actively transported from
the tubular fluid in a given period.
• This maximum reabsorption rate is designated
as the tubular maximum, or Tm
• With the exception of Na+, all actively
reabsorbed substances have a Tm
Active Reabsorption
• Glucose is an example of an actively reabsorbed
substance that is not regulated by the kidneys
• At a constant GFR, the filtered load of glucose is
directly proportional to the plasma glucose
concentration
• When more glucose is filtered per minute than
can be reabsorbed because the Tm has been
exceeded, the maximum amount is reabsorbed,
whereas the rest stays in the filtrate to be
excreted
Active Reabsorption
• In reality, glucose often starts spilling into the urine at
glucose concentrations of 180 mg/100 mL and above
• The kidneys do not regulate glucose because they do
not maintain glucose at some specific plasma
concentration.
• Instead, this concentration is normally regulated by
endocrine and liver mechanisms, with the kidneys
merely maintaining whatever plasma glucose
concentration is set by these other mechanisms
• The same principle holds true for other organic plasma
nutrients, such as amino acids and water-soluble
vitamins
Active Reabsorption
• phosphate (PO43-) and calcium (Ca2+) are
regulated by kidneys because the renal
thresholds of these inorganic ions equal their
normal plasma concentrations.
• The transport carriers for these electrolytes are
located in the proximal tubule
• Parathyroid hormone can alter the renal
thresholds for PO43- and Ca2+, thus adjusting the
quantity of these electrolytes conserved,
depending on the body’s momentary needs
Co-Transport
• Active Na+ reabsorption is responsible for the
passive reabsorption of Cl2, H2O, and urea
• For the most part, Cl2 passes between, not
through, the tubular cells (through “leaky”
tight junctions)
Water Reabsorption
• Most water (65%) is reabsorbed in proximal
tubule
• Water is reabsorbed in proximal tubule & loop
of Henle regardless of water load in body and
not subject to regulation
• The extent of reabsorption in the distal and
collecting tubules is under direct hormonal
control, depending on the body’s state of
hydration
Water Reabsorption
• During reabsorption,
H2O passes primarily
through aquaporins
(AQPs), or water
channels
• The water channels in
AQP-1, are always open,
accounting for the high
H2O permeability of this
region
Water Reabsorption
The AQP-2 channels in the
principal cells in the distal
parts of the nephron, in
contrast, are regulated by
the hormone vasopressin,
accounting for the
variable H2O reabsorption
in this region
Water Reabsorption
The main driving force for
H2O reabsorption in the
proximal tubule is a
compartment of
hypertonicity in the lateral
spaces between the
tubular cells established
by the basolateral pump’s
active extrusion of Na+
Water Reabsorption
• In the tubular 
concentration of sodium
is low while in lateral
spaces it is concentrated
• This osmotic gradient
induces the passive net
flow of H2O from the
lumen into the lateral
spaces, either through
the cells or intercellularly
through “leaky” tight
junctions.
Water Reabsorption
• Water also osmotically
follows other
preferentially reabsorbed
solutes such as glucose
(which is also Na+
dependent), but the
direct influence of Na+
reabsorption on passive
H2O reabsorption is
quantitatively more
important
Water Reabsorption
The concentration of
plasma proteins, which is
responsible for the
plasma-colloid osmotic
pressure, is elevated in
the blood entering the
because of the extensive
filtration of H2O through
the glomerular capillaries
upstream.
Water Reabsorption
The plasma proteins left
behind in the glomerulus
are concentrated into a
smaller volume of plasma
H2O, increasing the
plasma-colloid osmotic
pressure of the unfiltered
blood that leaves the
glomerulus and enters the
Urea Reabsorption
• Passive reabsorption of
urea is indirectly linked to
active Na+ reabsoprtion
• The osmotically induced
reabsorption of H2O in
the proximal tubule
secondary to active Na1
reabsorption produces a
concentration gradient
for urea that favors
passive reabsorption of
this waste
Urea Reabsorption
• Urea’s concentration as it
is filtered at the
glomerulus is identical to
its concentration in the
plasma entering the
• Because the walls of the
proximaltubules are only
somewhat permeable to
urea, only about 50% of
the filtered urea is
passively reabsorbed by
this means
Urea Recycling
• Urea is reabsorbed and secreted in the nephron by
diffusion, either simple or facilitated, depending on the
segment of the nephron.
• Fifty percent of the filtered urea is reabsorbed in the
proximal tubule by simple diffusion.
• Urea is secreted into the thin descending limb of the
loop of Henle by simple diffusion (from the high
concentration of urea in the medullary interstitial
fluid).
• The distal tubule, cortical collecting ducts, and outer
medullary collecting ducts are impermeable to urea;
thus, no urea is reabsorbed by these segments.
Urea Recycling
• ADH stimulates a facilitated diffusion transporter
for urea (UT1) in the inner medullary collecting
ducts.
• Urea reabsorption from inner medullary
collecting ducts contributes to urea recycling in
the inner medulla and to the addition of urea to
the corticopapillary osmotic gradient
• Urea recycling from the inner medullary
collecting ducts into the medullary interstitial
fluid also is augmented by ADH (by stimulating
the UT1 transporter
Excretion of Metabolic Waste
• The other filtered waste products besides urea, such as
uric acid, creatinine, and phenols (derived from many
foods) are likewise concentrated in the tubular fluid as
H2O leaves the filtrate to enter the plasma
• But urea molecules, being the smallest of the waste
products, are the only wastes passively reabsorbed by
this concentrating effect
• This excretion of metabolic wastes is not subject to
physiologic control, but when renal function is normal,
the excretory processes proceed at a satisfactory rate.
TUBULAR SECRETION
Tubular Secretion
• Also involves transepithelial transport
• Supplemental mechanism that hastens
elimination of these compounds from the
body
• Most important substances secreted:
hydrogen ion (H+), potassium ion (K+), and
organic anions and cations
Hydrogen Ion
• Hydrogen ion secreted into the tubular fluid is
eliminated from the body in the urine.
• Hydrogen ion can be secreted by the proximal,
distal, and collecting tubules, with the extent
of H+ secretion depending on the acidity of
the body fluids (too acidic  secretion
increases)
Potassium Ion
• 98% of the K+ is in the
intracellular fluid because
the Na+–K+ pump actively
transports K+ into the
cells
• Potassium is actively
reabsorbed in the
proximal tubule and
actively secreted by
principal cells in the distal
and collecting tubules.
Potassium Ion
• Early in the tubule, K+ is
constantly reabsorbed
without regulation,
whereas K+ secretion later
in the tubule by the
principal cells is variable
and subject to regulation.
• Most K+ in the urine is
derived from controlled
K+ secretion in the distal
parts of the nephron
rather than from filtration
Potassium Ion
• Potassium ion secretion in
the principal cells of the
distal and collecting
tubules is coupled to Na+
reabsorption by the
energy-dependent
basolateral Na+–K+pump
• The resulting high
intracellular K+
concentration favors net
movement of K+ from the
cells into the tubular
lumen.
Potassium Ion
• Movement across the
luminal membrane
occurs passively
through the large
number of K+ leak
channels in this barrier
in the distal and
collecting tubules
Potassium Ion
• In the principal cells of
the distal and collecting
tubules, the K+ channels
are concentrated in the
luminal membrane,
providing a route for K+
pumped into the cell to
exit into the lumen,
thus being secreted
Potassium Ion
• In the proximal tubule,
the K+ leak channels are
located primarily in the
basolateral membrane.
• As a result, K+ pumped
into the cell from the
lateral space by the Na+–
K+ pump simply moves
back out into the lateral
space through these
channels
Potassium Ion
• Most important factor
that alter rate of
potassium secretion is
aldosterone
• This hormone stimulates
K+ secretion by the
principal tubular cells late
in the nephron while
simultaneously enhancing
these cells’ reabsorption
of Na+
Potassium Ion
• K+ secretion can be
inadvertently
stimulated as a result of
increased aldosterone
activity brought about
by Na+ depletion, ECF
volume reduction, or a
fall in arterial blood
pressure totally
unrelated to K+ balance
Potassium Ion
• Another factor that can
inadvertently alter the
magnitude of K+ secretion is
the acid– base status of the
body
• The intercalated cells in the
distal portions of the
nephron secrete either K+ or
H+
• An increased rate of
secretion of either K+ or H+
is accompanied by a
decreased rate of secretion
of the other ion
Secretory Carriers
The proximal tubule contains two distinct types
of secretory carriers, one for the secretion of
organic anions and a separate system for
secretion of organic cations
Functions of Organic Ion Secretory
Systems
1. Facilitate excretion of blood-borne chemical
messengers such as PGE or Epinephrine
2. Some organic ions are poorly soluble in water
(bound to plasma proteins). Tubular
secretion facilitates elimination of these ions.
3. Eliminate many foreign compounds from the
body
Urine Excretion & Plasma Clearance
• Of the 125 mL of plasma filtered per minute,
typically 124 mL/min are reabsorbed, so the
final quantity of urine formed averages 1
mL/min.
• Thus, of the 180 liters filtered per day, 1.5
litersof urine are excreted.
URINE EXCRETION AND PLASMA
CLEARANCE
• Plasma clearance of any substance is defined as
the volume of plasma completely cleared of that
substance by the kidneys per minute.
• It refers to volume of plasma from which that
amount was removed.
• inulin is a harmless foreign carbohydrate and all
glomerular filtrate is cleared of inulin, the volume
of plasma cleared of inulin per minute equals the
volume of plasma filtered per minute – that is the
GFR
• Although determination of inulin plasma
clearance is accurate and straightforward, it is not
very convenient because inulin must be infused
continuously throughout the determination to
maintain a constant plasma concentration
• Therefore, creatinine clearance is used
• It is produced at a relatively constant rate, freely
filtered, not reabsorbed but is slightly secreted
• If a substance is filtered and reabsorbed but
not secreted, its plasma clearance rate is
always less than the GFR  Glucose
• If a substance is filtered and secreted but not
reabsorbed, its plasma clearance rate is
always greater than the GFR  H+
• The ECF osmolarity (solute concentration)
depends on the relative amount of H2O
compared to solute
• Isotonic  300 milliosmols, less than that 
hypotonic, more than that  hypertonic
• A large vertical osmotic
gradient is uniquely
maintained in the
interstitial fluid of the
medulla of each kidney
• This gradient enables the
kidneys to produce urine
that ranges in
concentration from 100
to 1200 mOsm/L,
depending on the body’s
state of hydration
• Flow in both the long loops of
Henle and the vasa recta is
considered countercurrent
because the flow in the two
closely adjacent limbs of the
loop moves in opposite
directions
• This arrangement, coupled
with the permeability and
transport characteristics of
these tubular segments, plays
a key role in the kidneys’
ability to produce urine of
varying concentrations
• The juxtamedullary
nephrons’ long loops of
Henle establish the vertical
osmotic gradient, their vasa
recta preserve this gradient
while providing blood to
the renal medulla, and the
collecting ducts of all
nephrons use the gradient,
in conjunction with the
hormone vasopressin, to
produce urine of varying
concentrations
• Collectively  Medullary
Countercurrent System
• Immediately after the
filtrate is formed,
uncontrolled osmotic
reabsorption of filtered
H2O occurs in the
proximal tubule
secondary to active Na+
reabsorption.
• As a result, by the end of
about 65% of the filtrate
has been reabsorbed
• An additional 15% of the
filtered H2O is obligatorily
reabsorbed from the loop
of Henle during the
establishment and
maintenance of the
vertical osmotic gradient,
with the osmolarity of the
tubular fluid being altered
in the process
• The descending limb of loop of Henle is highly
permeable to H2O (via abundant, always-open
AQP-1 water channels) and does not actively
extrude Na+—that is, it does not reabsorb Na1. (It
is the only segment of the entire tubule that does
not do so.)
• The ascending limb actively transports NaCl out
of the tubular lumen into the surrounding
interstitial fluid and is always impermeable to
H2O, so salt leaves the tubular fluid without H2O
osmotically following along
• The active salt pump in the ascending limb can
transport NaCl out of the lumen until the surrounding
interstitial fluid is 200 mOsm/L more concentrated
than the tubular fluid in this limb.
• When the ascending limb pump starts actively
extruding NaCl, the medullary interstitial fluid becomes
hypertonic.
• Water cannot follow osmotically from the ascending
limb because this limb is impermeable to H2O.
• However, net diffusion of H2O does occur from the
descending limb into the interstitial fluid
• In descending loop  still
isotonic but water molecules
move by osmosis into the
more concentrated interstitial
fluid
• Thus, the tubular fluid
entering the loop of Henle
immediately starts to become
more concentrated as it loses
H2O.
• At equilibrium, the osmolarity
of the ascending limb fluid is
200 mOsm/L and the
osmolarities of the interstitial
fluid and descending limb fluid
are equal at 400 mOsm/L
• The fluid in the descending
limb becomes progressively
more hypertonic until it
reaches a maximum
concentration of 1200
mOsm/L at the bottom of the
loop, four times the normal
concentration of body fluids.
• Because the interstitial fluid
always achieves equilibrium
with the descending limb, an
incremental vertical
concentration gradient ranging
from 300 to 1200 mOsm/L is
likewise established in the
medullary interstitial fluid
• In contrast, the
concentration of the tubular
fluid progressively decreases
in the ascending limb as
NaCl is pumped out but H2O
is unable to follow.
• In fact, the tubular fluid even
becomes hypotonic before
leaving the ascending limb
to enter the distal tubule at
a concentration of 100
mOsm/L, one third the
normal concentration of
body fluids
• Even though the ascending limb pump can
generate a gradient of only 200 mOsm/L, this
effect is multiplied into a large vertical
gradient because of the countercurrent flow
within the loop.
• This concentrating mechanism accomplished
by the loop of Henle is known as
countercurrent multiplication
Once the incremental medullary gradient is
established, it stays constant because of the
continuous flow of fluid, coupled with the
ongoing ascending limb active transport and the
accompanying descending limb passive fluxes
Benefits of Countercurrent
Multiplication
• First, it establishes a vertical osmotic gradient in
the medullary interstitial fluid. This gradient, in
turn, is used by the collecting ducts to
concentrate the tubular fluid so that a urine more
concentrated than normal body fluids can be
excreted.
• Second, because the fluid is hypotonic as it enters
the distal parts of the tubule, the kidneys can
excrete a urine more dilute than normal body
fluids.
Vasopressin
• The fluid leaving the loop of Henle enters the
distal tubule at 100 mOsm/L, so it is hypotonic to
the surrounding isotonic (300 mOsm/L)
interstitial fluid of the renal cortex through which
the distal tubule passes.
• The distal tubule then empties into the collecting
duct, which is bathed by progressively increasing
concentrations (300 to 1200 mOsm/L) of the
surrounding interstitial fluid as it descends
through the medulla.
Vasopressin
• For H2O absorption to occur across a segment
of the tubule, two criteria must be met:
(1) an osmotic gradient must exist across the
tubule
(2) the tubular segment must be permeable to
H2O.
• The distal and collecting tubules are
impermeable to H2O except in the presence
of vasopressin or ADH
Regulation of Water Reabsorption In
Response to A Water Deficit
• The hypotonic tubular fluid
entering the distal part of
the nephron can lose
progressively more H2O by
osmosis into the interstitial
fluid as the tubular fluid
first flows through the
isotonic cortex and then is
exposed to the ever-
increasing osmolarity of the
medullary interstitial fluid
as it plunges toward the
renal pelvis
• Consequently, the
tubular fluid loses more
H2O by osmosis and
becomes further
concentrated; only to
move farther forward,
be exposed to an even
higher interstitial fluid
osmolarity, and lose
even more H2O; and so
on.
• Under the influence of
maximum levels of
vasopressin, the tubular fluid
can be concentrated up to
1200 mOsm/L by the end of
the collecting ducts
• As little as 0.3 mL of urine may
be formed each minute, less
than one third the normal
urine flow rate of 1 mL/min.
• The reabsorbed H2O entering
the medullary interstitial fluid
is picked up by the peritubular
capillaries and returned to the
general circulation, thus being
conserved for the body
• Although vasopressin
promotes H2O conservation
by the body, it cannot halt
urine production, even when
a person is not taking in any
H2O, because a minimum
volume of H2O must be
excreted with the solute
wastes
• Thus, under maximal
vasopressin influence, 99.7%
of the 180 liters of plasma
H2O filtered per day is
returned to the blood, with
an obligatory H2O loss of 0.5
liter
Response to A Water Excess
• Under these circumstances, no
vasopressin is secreted, so the distal
and collecting tubules remain
impermeable to H2O. The tubular
fluid entering the distal tubule is
hypotonic (100mOsm/L)
• The net result is a large volume of
dilute urine, which helps rid the
body of excess H2O.
• Urine osmolarity may be as low as
100 mOsm/L—the same as in the
fluid entering the distal tubule.
• Urine flow may be increased up to
25 mL/min in the absence of
vasopressin, compared to the
normal urine production of 1
mL/min
Countercurrent Exchange
• It is important that circulation of blood through the
medulla does not disturb the vertical gradient of
hypertonicity established by the loops of Henle
• Because capillaries are freely permeable to NaCl and
H2O, the blood would progressively pick up salt and
lose H2O through passive fluxes down concentration
and osmotic gradients as it flowed through the depths
of the medulla
• It would be impossible to establish and maintain the
medullary hypertonic gradient because the NaCl
pumped into the medullary interstitial fluid would
continuously be carried away by the circulation.
Countercurrent Exchange
• This dilemma is avoided by the hairpin
construction of the vasa recta, which, by
looping back through the concentration
gradient in reverse, allows the blood to leave
the medulla and enter the renal vein
essentially isotonic to incoming arterial blood
• It does not establish the concentration
gradient. Rather, it preserves (prevents the
dissolution of) the gradient
Micturition
• Micturition is the process by which the urinary bladder
empties when it becomes filled.
• This involves two main steps: First, the bladder fills
progressively until the tension in its walls rises above a
threshold level; this elicits the second step, which is a
nervous reflex called the micturition reflex that
empties the bladder or, if this fails, at least causes a
conscious desire to urinate.
• Although the micturition reflex is an autonomic spinal
cord reflex, it can also be inhibited or facilitated by
centers in the cerebral cortex or brain stem.
Micturition
• The urinary bladder is a
smooth muscle chamber
composed of two main
parts: the body and the
neck passing inferiorly and
anteriorly into the
urogenital triangle and
connecting with the
urethra.
• The lower part of the
bladder neck is also called
the posterior urethra
because of its relation to
the urethra
Micturition
• The smooth muscle of the
bladder is called the
detrusor muscle. Its
muscle fibers extend in all
directions and, when
contracted, can increase
the pressure in the
bladder to 40 to 60 mm
Hg. Thus, contraction of
the detrusor muscle is a
major step in emptying
the bladder
Micturition
• The bladder neck
(posterior urethra) is 2
to 3 centimeters long,
and its wall is composed
of detrusor muscle
interlaced with a large
amount of elastic
tissue. The muscle in
this area is called the
internal sphincter.
Micturition
• Beyond the posterior
urethra, the urethra
passes through the
urogenital diaphragm,
which contains a layer
of muscle called the
external sphincter of
the bladder.
Micturition
• The principal nerve
supply of the bladder is
by way of the pelvic
nerves, which connect
with the spinal cord
through the sacral
plexus, mainly
connecting with cord
segments S2 and S3
Micturition
• Sensory nerves  detect
the degree of stretch in
bladder wall
• Motor 
parasympathetic nerves
• There are also other
nerves such as pudendal
nerves  external
bladder sphincter and
somatic nerve fibers 
innervate and control
voluntary skeletal muscles
of the sphincter
Micturition
• Bladder receives
sympathetic innervation
from the sympathetic
chain through the
hypogastric nerves,
connecting mainly with
the L2 segment of the
spinal cord
Micturition Reflex
• Bladder in adult can accommodate 250 ml to 400
ml of urine; Up to 500 ml
• When the bladder is only partially filled, these
micturition contractions usually relax
spontaneously after a fraction of a minute, the
detrusor muscles stop contracting, and pressure
falls back to the baseline.
• As the bladder continues to fill, the micturition
reflexes become more frequent and cause greater
contractions of the detrusor muscle
Micturition Reflex
• Once a micturition reflex begins, it is “self-regenerative.”
• That is, initial contraction of the bladder activates the
stretch receptors to cause a greater increase in sensory
impulses from the bladder and posterior urethra, which
causes a further increase in reflex contraction of the
bladder
• Thus, the cycle is repeated again and again until the
bladder has reached a strong degree of contraction.
• Then, after a few seconds to more than a minute, the self-
regenerative reflex begins to fatigue and the regenerative
cycle of the micturition reflex ceases, permitting the
bladder to relax.
Micturition Reflex
Once the micturition reflex becomes powerful
enough, it causes another reflex, which passes
through the pudendal nerves to the external
sphincter to inhibit it. If this inhibition is more
potent in the brain than the voluntary
constrictor signals to the external sphincter,
urination will occur. If not, urination will not
occur until the bladder fills still further and the
micturition reflex becomes more powerful
Micturition Reflex
The micturition reflex is an autonomic spinal
cord reflex, but it can be inhibited or facilitated
by centers in the brain. These centers include (1)
strong facilitative and inhibitory centers in the
brain stem, located mainly in the pons, and (2)
several centers located in the cerebral cortex
that are mainly inhibitory but can become
excitatory.
Micturition Reflex
Higher centers normally exert final control of micturition
as follows:
1. The higher centers keep the micturition reflex
partially inhibited, except when micturition is desired.
2. The higher centers can prevent micturition, even if
the micturition reflex occurs, by tonic contraction of
the external bladder sphincter until a convenient time
presents itself.
3. When it is time to urinate, the cortical centers can
facilitate the sacral micturition centers to help initiate
a micturition reflex and at the same time inhibit the
external urinary sphincter so that urination can occur.
Micturition Reflex
Voluntary urination is usually initiated in the
following way: First, a person voluntarily contracts
his or her abdominal muscles, which increases the
pressure in the bladder and allows extra urine to
enter the bladder neck and posterior urethra under
pressure, thus stretching their walls. This stimulates
the stretch receptors, which excites the micturition
reflex and simultaneously inhibits the external
urethral sphincter. Ordinarily, all the urine will be
emptied, with rarely more than 5 to 10 milliliters
left in the bladder.
Basic Knowledge on Spermatogenesis
Basic Knowledge on Spermatogenesis
Effects of Testosterone
Male Sexual Act
Consists of 3 phases:
1. Erection
2. Emission
3. Ejaculation
4. Resolution
Erection
• Penile erection is the first effect of male sexual stimulation, and the
degree of erection is proportional to the degree of stimulation, whether
psychic or physical.
• Erection is caused by parasympathetic impulses that pass from the sacral
portion of the spinal cord through the pelvic nerves to the penis.
• These parasympathetic nerve fibers are believed to release nitric oxide
and/or vasoactive intestinal peptide in addition to acetylcholine.
• Nitric oxide activates the enzyme guanylyl cyclase, causing increased
formation of cyclic guanosine monophosphate (GMP).
• The cyclic GMP especially relaxes the arteries of the penis and the
trabecular meshwork of smooth muscle fibers in the erectile tissue of the
corpora cavernosa and corpus spongiosum in the shaft of the penis
• As the vascular smooth muscles relax, blood flow into the penis increases,
causing release of nitric oxide from the vascular endothelial cells and
further vasodilation
Erection
• The erectile tissue of the penis consists of large
cavernous sinusoids, which are normally relatively
empty of blood but become dilated tremendously
when arterial blood flows rapidly into them under
pressure while the venous outflow is partially
occluded.
• Also, the erectile bodies, especially the two corpora
cavernosa, are surrounded by strong fibrous coats;
therefore, high pressure within the sinusoids causes
ballooning of the erectile tissue to such an extent that
the penis becomes hard and elongated. This is the
phenomenon of erection
Emission and Ejaculation
Emission and ejaculation are the culmination of
the male sexual act. When the sexual stimulus
becomes extremely intense, the reflex centers of
the spinal cord begin to emit sympathetic
impulses that leave the cord at T-12 to L-2 and
pass to the genital organs through the
hypogastric and pelvic sympathetic nerve
plexuses to initiate emission, the forerunner of
ejaculation
Emission
Emission begins with contraction of the vas
deferens and the ampulla to cause expulsion of
sperm into the internal urethra. Then, contractions
of the muscular coat of the prostate gland followed
by contraction of the seminal vesicles expel
prostatic and seminal fluid also into the urethra,
forcing the sperm forward. All these fluids mix in
the internal urethra with mucus already secreted by
the bulbourethral glands to form the semen. The
process to this point is emission
Ejaculation
• The filling of the internal urethra with semen elicits sensory
signals that are transmitted through the pudendal nerves to
the sacral regions of the cord, giving the feeling of sudden
fullness in the internal genital organs.
• Also, these sensory signals further excite rhythmical
contraction of the internal genital organs and cause
contraction of the ischiocavernosus and bulbocavernosus
muscles that compress the bases of the penile erectile
tissue.
• These effects together cause rhythmical, wavelike increases
in pressure in both the erectile tissue of the penis and the
genital ducts and urethra, which “ejaculate” the semen
from the urethra to the exterior. This final process is called
ejaculation.
Ejaculation
At the same time, rhythmical contractions of the
pelvic muscles and even of some of the muscles
of the body trunk cause thrusting movements of
the pelvis and penis, which also help propel the
semen into the deepest recesses of the vagina
and perhaps even slightly into the cervix of the
uterus
Orgasm and Resolution
This entire period of emission and ejaculation is
called the male orgasm. At its termination, the
male sexual excitement disappears almost
entirely within 1 to 2 minutes and erection
ceases, a process called resolution.
Summary of Acid-Base Disorders
Sources
• Sherwood 8th Edition
• Guyton and Hall 12th Edition
• BRS Physiology 6th Edition

Physiology of Kidney Functions and Nephron Structure

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