Dr IHSAN EBRAHIM/COLLEGE OF PHARMACY

Renal Physiology
Each kidney contains approximately 1 million similar subunits called
nephrons. Each nephron consists of (1) renal corpuscle, (2) Renal
tubule that extends out from the renal corpuscle..

1- Renal capsule: Each renal corpuscle contains a compact tuft of

interconnected capillary loops called the glomerulus Each
glomerulus is supplied with blood by an arteriole called an
afferent arteriole. The glomerulus protrudes into a fluid-filled
capsule called Bowman’s capsule.. As blood flows through the
glomerulus, a portion of the plasma filters into Bowman’s capsule.
The remaining blood then leaves the glomerulus by another
arteriole, the efferent arteriole.

. Fluid filters first across the endothelial cells, then through the basement
membrane, and finally between the foot processes of the podocytes.
In addition to the capillary endothelial cells and the podocytes, there is a
third cell type, mesangial cells, which are modified smooth-muscle cells
that surround the glomerular capillary loops but are not
part of the filtration pathway.
2-Renal tubule
the segment of the tubule that drains Bowman’s capsule is the proximal
tubule. The next portion of the tubule is the loop of Henle, which is
consisting of a descending limb coming from the proximal tubule and an
ascending limb leading to the next tubular segment, the distal
convoluted tubule. Fluid flows from the distal convoluted tubule into the
collecting duct system, the first portion of which is the connecting
tubule, followed by the cortical collecting duct and then the medullary
collecting duct .

There are important regional differences in the kidney .The outer portion
is the renal cortex, and the inner portion the renal medulla. The cortex
contains all the renal corpuscles. The loops of Henle extend from the
cortex for varying distances down into the medulla. The medullary
collecting ducts pass through the medulla on their way to the renal pelvis.
All along its length, each tubule is surrounded by capillaries, called the
peritubular capillaries.
there is a patch of cells in the wall of the ascending limb called the
macula densa, and the wall of the afferent arteriole contains secretory
cells known as juxtaglomerular (JG) cells. The combination of macula
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densa and juxtaglomerular cells is known as the juxtaglomerular

apparatus (JGA) .The juxtaglomerular cells secrete the hormone renin

Structure of nephrone
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Glomerular Filtration Rate

the filtration of plasma from the glomerular capillaries into Bowman’s
space. This process is termed glomerular filtration, and the filtrate is
called the glomerular filtrate .

The volume of fluid filtered from the glomeruli into Bowman’s space per
unit time is known as the glomerular filtration rate (GFR). GFR is
determined not only by the net filtration pressure but also by the
permeability of the membranes and the surface area available for
filtration
. It is possible to measure the total amount of any nonprotein substance
(assuming also that the substance is not bound to protein) filtered into
Bowman’s space by multiplying the GFR by the plasma concentration of
the substance. This amount is called the filtered
load of the substance. For example, if the GFR is 180 L/day and plasma
glucose concentration is 1 g/L, then the filtered load of glucose is 180
L/day _ 1 g/L _ 180 g/day.
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. Whenever the quantity of a substance excreted in the urine is less than

the filtered load, tubular reabsorption must have occurred. Conversely, if
the amount excreted in the urine is greater than the filtered load, tubular
secretion must have occurred.

The Concept of Renal Clearance

The renal clearance of any substance is the volume of plasma from which
that substance is completely removed (“cleared”) by the kidneys per unit
time. Every substance has its own distinct clearance
value, but the units are always in volume of plasma per time. The basic
clearance formula for any substance S is

Clearance of S _

the mass of S excreted per unit time is equal to the urine concentration of
S multiplied by the urine volume during that time, the formula for the
clearance of S becomes

____
where CS _ clearance of S
US _ urine concentration of S
V _ urine volume per unit time
PS _ plasma concentration of S

Let us take the particularly important example of a polysaccharide named

inulin. This substance is an important research tool in renal physiology
because its clearance is equal to the glomerular filtration rate. It is not
found normally in the body, but it administered intravenously to a person
at a rate sufficient to maintain plasma concentration constant at 4 mg/L.
Urine collected over a 1-h period has a volume of 0.1 L and an inulin
concentration of 300 mg/L; thus, inulin excretion equals 0.1 L/h _ 300
mg/L, or 30 mg/h.

How much plasma had to be completely cleared of its inulin to supply

this 30 mg/h? We simply divide 30 mg/h by the plasma concentration, 4
mg/L, to obtain the volume cleared—7.5 L/h. In other words, we are
calculating the inulin clearance (CIn) from the measured
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urine volume per time (V), urine inulin concentration (UIn), and plasma
inulin concentration (PIn):

For clinical purposes, the creatinine clearance (CCr) is commonly used

to approximate the GFR as follows. The waste product creatinine
produced by muscle is filtered at the renal corpuscle and does not
undergo reabsorption. It does undergo a small amount of secretion,
however, so that some plasma is cleared of its creatinine by secretion.
Accordingly, the CCr overestimates the GFR but is close enough to be
highly useful

Regulation of Glomerular Filtration Rate

Vasoconstriction or dilation of afferent arterioles affects the rate of blood
flow to the glomerulus, and thus affects the glomerular filtration rate.
Changes in the diameter of the afferent arterioles result from both
extrinsic regulatory mechanisms (produced by sympathetic nerve
innervation), and intrinsic regulatory mechanisms (those within the
kidneys, also termed renal autoregulation). These mechanisms are
needed to ensure that the GFR will be high enough to allow the kidneys
to eliminate wastes and regulate blood pressure, but not so high as to
cause excessive water loss.
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1-Sympathetic Nerve Effects (Extrinsi regulatory mechanism)

An increase in sympathetic nerve activity, as occurs during the fight-or-
flight reaction and exercise, stimulates constriction of afferent arterioles.
This helps to preserve blood volume and to divert blood to the muscles
and heart. A similar effect occurs during cardiovascular shock, when
sympathetic nerve activity stimulates vasoconstriction.

2-Renal Autoregulation (Intrinsic regulatory mechanism)

. The ability of the kidneys to maintain a relatively constant GFR in the
face of fluctuating blood pressures is called renal autoregulation.

Renal autoregulation is achieved through the effects of locally produced

chemicals on the afferent arterioles .When systemic arterial pressure falls
toward a mean of 70 mmHg, the afferent arterioles dilate, and when the
pressure rises, the afferent arterioles constrict.

. Autoregulation is also achieved through a negative feedback relationship

between the afferent arterioles and the volume of fluid in the filtrate. An
increased flow of filtrate is sensed by a special group of cells called the
macula densa in the thick portion of the ascending limb When the macula
densa senses an increased flow of filtrate, it signals the afferent arterioles
to constrict. This lowers the GFR, thereby decreasing the formation of
filtrate in a process called tubuloglomerular feedback.
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Reabsorption of Salt and Water

. The return of filtered molecules from the tubules to the blood is

called reabsorption .
Most of the salt and water filtered from the blood is returned to the
blood through the wall of the proximal tubule. The reabsorption of water
occurs by osmosis, in which water follows the transport of NaCl from the
tubule into the surrounding capillaries.

Most of the water remaining in the filtrate is reabsorbed across the wall
of the collecting duct in the renal medulla. This occurs as a result of the
high osmotic pressure of the surrounding tissue fluid, which is produced
by transport processes in the loop of Henle.
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Although about 180 L of glomerular ultrafiltrate are produced each day,

the kidneys normally excrete only 1 to 2 L of urine in a 24-hour period.
Approximately 99% of the filtrate must thus be returned to the vascular
system, while 1% is excreted in the urine. The urine volume, however,
varies according to the needs of the body

. Reabsorption by osmosis cannot occur unless the solute concentrations

of plasma in the peritubular capillaries and the filtrate are altered by
active transport processes. This is achieved by the active transport of Na+
from the filtrate to the peritubular blood.

Active Transport of Na

. The epithelial cells of the tubule, however, have a much lower Na+
concentration. This lower Na+ concentration is partially due to the low
permeability of the plasma membrane to Na+ and partially due to the
active transport of Na+ out of the cell by Na+/K+ pumps, .

In the cells of the proximal tubule, the Na+/K+ pumps are located in the
basal and lateral sides of the plasma membrane
. As a result of the action of these active transport pumps, a concentration
gradient is created that favors the diffusion of Na+ from the tubular fluid
across the apical plasma membranes and into the epithelial cells of the
proximal tubule. The Na+ is then extruded into the surrounding tissue
fluid by the Na+/K+ pumps. The transport of Na+ from the tubular fluid
to the interstitial (tissue) fluid surrounding the proximal tubule creates a
electrical gradient.

This electrical gradient favors the passive transport of Cl– toward the
higher Na+ concentration in the interstitial fluid.. As a result of the
accumulation of NaCl, the osmolality and osmotic pressure of the
interstitial fluid surrounding the epithelial cells are increased above those
of the tubular fluid.

. An osmotic gradient is thus created between the tubular fluid and the
interstitial fluid surrounding the proximal tubule. Since the cells of the
proximal tubule are permeable to water, water moves by osmosis from
the tubular fluid into the epithelial cells and then across the basal and
lateral sides of the epithelial cells into the interstitial fluid.
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Reabsorption of Glucose

Glucose and amino acids in the blood are easily filtered by the glomeruli
into the renal tubules. These molecules, however, are usually not present
in the urine. It can therefore be concluded that filtered glucose and amino
acids are normally completely reabsorbed by the nephrons. This occurs in
the proximal tubule by secondary active transport, which is mediated by
membrane carriers that cotransport glucose and Na+, or amino acids and
Na+.
Carrier-mediated transport displays the property of saturation.
This means that when the transported molecule (such as glucose) is
present in sufficiently high concentrations, all of the carriers become
occupied and the transport rate reaches a maximal value. The
concentration of transported molecules needed to just saturate the carriers
and achieve the maximal transport rate is called the transport maximum
(abbreviated Tm). The carriers for glucose and amino acids in the renal
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tubules are not normally saturated and so are able to remove the filtered
molecules completely.
The Tm for glucose, for example, averages 375 mg per minute, which is
well above the normal rate at which glucose is delivered to the tubules.
Glycosuria
Glucose appears in the urine—a condition called glycosuria— when
more glucose passes through the tubules than can be reabsorbed. This
occurs when the plasma glucose concentration reaches 180 to 200 mg per
100 ml..
The renal plasma threshold is the minimum plasma concentration of a
substance that results in the excretion of that substance in the urine. The
renal plasma threshold for glucose, for example, is 180 to 200 mg per 100
ml.
When this hyperglycemia results in glycosuria, the disease is called
diabetes mellitus. A person with uncontrolled diabetes mellitus also
excretes a large volume of urine because the excreted glucose carries
water with it as a result of the osmotic pressure it generates in the tubules.
This condition should not be confused with diabetes insipidus in which a
large volume of dilute urine is excreted as a result of inadequate ADH
secretion

Role of Aldosterone in Na/KBalance

Renal reabsorption of Na+ and secretion of K+ are regulated by
aldosterone, the principal mineralocorticoid secreted by the adrenal
cortex

1-Sodium Reabsorption
Although 90% of the filtered sodium is reabsorbed in the early
region of the nephron, the amount left in the filtrate delivered to
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the distal convoluted tubule is still quite large.. When aldosterone is

secreted in maximal amounts, by contrast, all of the sodium delivered to
the distal tubule is reabsorbed.

Aldosterone stimulates Na+ reabsorption to some degree in the late distal

convoluted tubule, but the primary site of aldosterone action is in the
cortical collecting duct. This is the initial portion of the collecting duct,
located in the renal cortex, which has different permeability properties
than the terminal portion of the collecting duct, located in the renal
medulla.

2-Potassium Secretion
About 90% of the filtered potassium is reabsorbed in the early regions
of the nephron (mainly from the proximal tubule).. Secretion of
potassium occurs in the parts of the nephron that are sensitive to
aldosterone—that is, in the late distal tubule and cortical collecting duct
As Na+ is reabsorbed in these regions of the nephron, the lumen of the
tubule becomes more negatively charged (–50 mV) compared to the
basolateral side.

This potential difference then drives the secretion of K+ into the tubule.
The amount of K+ secretion into the late distal tubule and cortical
collecting duct depends on: (1) the amount of Na+ delivered
to these regions of the nephron; and (2) the amount of aldosterone
secreted. If the blood concentration of K+ rises, this will stimulate
increased aldosterone secretion from the adrenal cortex.

. Control of Aldosterone Secretion

1-Regulation of Renin Secretion

An inadequate dietary intake of salt (NaCl) is always accompanied by a
fall in blood volume. This is because the decreased plasma concentration
(osmolality) inhibits ADH secretion. With less ADH, less water is
reabsorbed through the collecting ducts and more is excreted in the urine.
The fall in blood volume and the fall in renal blood flow that result cause
increased renin secretion. Increased renin secretion is believed to be due
in part to the direct effect of blood pressure on the granular cells, which
may function as baroreceptors in the afferent arterioles.
An increased secretion of renin acts, via the increased production
of angiotensin II, to stimulate aldosterone secretion. Consequently, less
sodium is excreted in the urine and more is retained in the blood.
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2-Role of the Macula Densa

The region of the ascending limb in contact with the granular cells
of the afferent arteriole is called the macula densa (fig. 17.25).
There is evidence that this region helps to inhibit renin secretion
when the blood Na+ concentration is raised.
The cells of the macula densa respond to the Na+ in the filtrate
delivered to the distal tubule.
. Through an effect on the macula densa, this increase in filtered Na+
inhibits the granular cells from secreting renin. Aldosterone secretion thus
decreases, and since less Na+ is reabsorbed in the cortical collecting
duct, more Na+ is excreted in the urine.
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3-Atrial Natriuretic Peptide

Expansion of the blood volume causes increased salt and water
excretion in the urine. This is partly due to an inhibition of aldosterone
secretion, as previously described. However, it is also caused by
increased secretion of a natriuretic hormone, a hormone that stimulates
salt excretion (natrium is Latin for sodium)—an action opposite to that of
aldosterone. atrial natriuretic peptide (ANP), also called atrial
natriuretic factor is produced by the atria of the heart and secreted in
response to the stretching of the atrial walls by increased blood volume.
In response to ANP action, the kidneys lower the blood volume by
excreting more of the salt and water filtered out of the blood by the
glomeruli.
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Effect of Antidiuretic Hormone (ADH)

The rate of water movement, however, is determined by the permeability
of the collecting duct to water. This depends on the number of
aquaporins (water channels) in the plasma membranes of the collecting
duct epithelial cells. In response to ADH, therefore, the collecting duct
becomes more permeable to water.

Diabetes insipidus is a disease associated with the inadequate secretion

or action of ADH.When the concentration of ADH is increased, the
collecting ducts become more permeable to water and more water is
reabsorbed. A decrease in ADH, conversely, results in less reabsorption
of water and thus in the excretion of a larger volume of more dilute urine
.ADH is produced by neurons in the hypothalamus and is released from
the posterior pituitary .The secretion of ADH is stimulated when
osmoreceptors in the hypothalamus respond to an increase in blood
osmolality. During dehydration, therefore, when the plasma becomes
more concentrated, increased secretion of ADH promotes increased
permeability of the collecting ducts to water.

Regulation of acid -base balance

The kidneys help to regulate the blood pH by excreting H+ in the urine
and by reabsorbing bicarbonate. The H+ enters the filtrate in two ways:
by filtration through the glomeruli and by secretion into the tubules. Most
of the H+ secretion occurs across the wall of the proximal tubule in
exchange for the reabsorption of Na+. This exchange is performed by a
transport carrier described as “antiport,” because it moves the Na+ and
H+ in opposite directions

when there is a lowering of plasma hydrogenion concentration (alkalosis)

for whatever reason, the kidneys’ homeostatic response is to excrete large
quantities of bicarbonate. This raises plasma hydrogen-ion concentration
back toward normal. In contrast, in response to a rise in plasma hydrogen-
ion concentration (acidosis), the kidneys do not excrete bicarbonate in
the urine, but instead kidney tubular cells produce new bicarbonate and
add it to the plasma. This lowers the plasma hydrogen-ion concentration
back toward normal.
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Bicarbonate cannot serve this buffering function because it is normally

completely reabsorbed. Instead, the buffering action of phosphates
(mainly HPO4 2–) and ammonia (NH3) provide the means for excreting
most of the H+ in the urine. Phosphate enters the urine by filtration.
Ammonia (whose presence is strongly evident in a diaper pail or kitty
litter box) is produced in the tubule cells by deamination of
amino acids.
NH3 + H+ → NH4 + (ammonium ion)
HPO4 2– + H+ → H2PO4
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