RENAL PHYSIOLOGY

Basic Principles of Renal

Physiology
 THE STRUCTURE OF THE
MAMMALIAN KIDNEY
The kidneys are a pair of bean-shaped organs found
in the lower back region behind the intestines. They
are 7-10cm long and are the major excretory and
osmoregulatory organs. Along with the ureter, bladder
and urethra, they make up the urinary system. It is in
this system that urine is produced and excreted by the
body via urination (micturition).
DIAGRAM OF THE URINARY SYSTEM
The renal artery brings blood with waste products to
the kidney to be cleansed. After the blood is
cleansed, it returns to the heart via the renal vein.
Wastes flow through the ureter as urine to the bladder
to be stored. When the bladder is full, stretch
receptors in its wall trigger a response, the muscles in
the wall contract and the sphincter muscles relax,
allowing the urine to be excreted through the urethra.
The kidneys are enclosed with a protective fibrous
capsule that shows distinct regions.
THE INTERNAL STRUCTURE OF THE KIDNEY
Cortex: The outer region. It has a more uneven texture than the medulla. The Renal
capsule, proximal convoluted tubule and distal convoluted tubule of the nephron are
located here.

Medulla: The inner region, consisting of zones known as „pyramids‟ which surround
the pelvis. The Loop of Henle and collecting ducts of the nephron are located here.

Pelvis: The central cavity. Urine formed after blood is cleansed is deposited here. This
cavity is continuous with the ureter so the urine goes directly to the bladder.
A DIAGRAM OF THE INTERNAL STRUCTURE
OF THE KIDNEY
 THE NEPHRON
The nephron is the functional unit found within
the kidneys. Each kidney is made up of millions
of microscopic nephrons, each with a rich blood
supply. To fully understand the function of the
kidney, the function of the nephron must be
studied and understood since it is this structure
that carries out excretion and osmoregulation.
DIAGRAM OF A NEPHRON
DIAGRAM OF A NEPHRON
 Each nephron has the following structures:

•Bowman‟s capsule (renal capsule)

•Proximal convoluted tubule

•Loop of Henle

•Distal convoluted tubule

•Collecting duct
BOWMAN‟S CAPSULE
Glomerulus: A mass of capillaries enclosed by the
Bowman‟s capsule.

Afferent arteriole: A branch of the renal artery that

supplies the glomerulus with blood.

Efferent arteriole: Takes blood away from the

glomerulus.

Malpighian body: The structure consisting of the

Bowman‟s capsule and the glomerulus.
There is a hydrostatic pressure in the glomerulus due to the
strong contraction of the left ventricle of the heart and the fact
that the diameter of the afferent arteriole is larger than that of
the efferent arteriole. The difference in diameters between the
two vessels raise the hydrostatic blood pressure. This causes
blood to filter into the Bowman‟s capsule under pressure in a
process called ultrafiltration. As a result, only molecules with
RMM less than 68,000 can enter the capsule (water, glucose,
amino acids, hormones, salt, urea), while the larger molecules
like plasma proteins and blood cells remain in the blood and
exit the Malpighian body via the efferent arteriole. The blood
must pass several filtrating barriers before it can enter the
capsule.
Endothelium of the capillary: these have small pores between the
sqamous cells that makes it more permeable than normal capillaries.
All the constituents of the blood plasma but blood cells can pass
through.

Basement membrane of the endothelium: this is a continuous layer

of organic material to which the endothelial cells are attached. Only
molecules with RMM less than 68,000 can pass through as this
membrane acts as a dialysing membrane. All constituents of the blood
plasma but the plasma proteins can pass through.

Podocytes: these are found on the inner wall of the Bowman‟s capsule
and are foot-like cells with many processes that wrap around the
capillary. There are gaps between the branches of the cell which
enables the free flow of substances that have passed through the
basement membrane, into the Bowman‟s capsule.
Diagrams of the podocytes and basement
membrane
Podocyte:
BASEMENT MEMBRANE
THE PROXIMAL CONVOLUTED TUBULE
This is the longest part of the nephron and is located in
the cortex of the kidney. It is surrounded by many
capillaries that are very close to the walls. Approximately
80% of the glomerular filtrate is reabsorbed here via
selective reabsorption. Cubical epithelial cells line the
tubule walls and have many microvilli on their free
surfaces which increase the surface area of the wall
exposed to the filtrate.
Fact: The total surface area of the Human proximal tubule
cells is 50m2!!!
There is a rich blood supply surrounding each
nephron, which is important for the
reabsorption process. The cubical epithelial
cells lining the tubule invaginates to form
intercellular and subcellular spaces next to the
basement membrane of the capillaries. Glucose
and amino acids are absorbed into the blood by
active transport across the infolded membranes
and subcellular spaces. These solutes diffuse
from the filtrate into the cells, then through to
the subcellular spaces and then into the
bloodstream. This sets up a concentration
gradient which is maintained as the reabsorbed
solutes are carried away by the flowing blood.
Other mineral ions are also actively reabsorbed the way
glucose and amino acids are. As so many of the solutes are
removed, the filtrate becomes hypotonic (lower
concentration of solute molecules) than the surrounding
blood, stimulating water to move via osmosis from the
filtrate to the blood. This leads to the filtrate and the blood
being isotonic (same solute concentrations) by the time the
filtrate reaches the end of the tubule. However, since urea is
not actively reabsorbed, its concentration in the filtrate is
much higher than in the blood and some of the urea
unavoidably diffuses back into the bloodstream and is taken
away.
 THE LOOP OF HENLE
This hairpin-bend structure has a descending limb
and an ascending limb and is found in the
medulla of the kidney. The descending limb has
thin walls permeable to water and penetrates deep
into the medulla but the ascending limb has
thicker, relatively impermeable walls that returns
to the cortex. Surrounding the loop is a network
of capillaries, one part of which has the same
hairpin structure and is called the vasa recta.
 Terminology:
Solution with greater
concentration of solute
molecules
Lower concentration of water
molecules
Lower solute potential
Lower water potential
hypertonic
Solution with lower
concentration of solute
molecules
Higher concentration of
water molecules
Higher solute potential
Higher water potential
hypotonic
 Need to know:
The loop of Henle works by making the concentration
of the interstitial tissues of the medulla hypertonic
(greater solute concentration) to the filtrate by actively
transporting chloride ions out of the filtrate into the
surroundings. Sodium ions passively follow. This occurs
in the thick part of the ascending limb.
The deeper part of the medulla near the pelvis is the
most concentrated and therefore has the lowest water
potential.
 The filtrate at the end of the proximal convoluted tubule,
entering the loop of Henle is isotonic. As it descends the loop,
it is carried through tissues of increasing solute concentration
and the permeable walls of the descending limb enables water
to leave the filtrate by osmosis and enter the surrounding
tissues. This water passes into the vasa recta and is carried
away in the blood, and this is possible because blood in the
vasa recta is flowing from deeper more concentrated regions
of the medulla so its water potential is lower than the filtrate
of the adjacent descending limb.
The continuous loss of water in the descending limb
causes the filtrate to have the same water potential as the
surrounding tissues by the time it reaches the hairpin bend,
both of which are hypertonic to the blood. The active removal
of sodium chloride in the ascending limb leaves the filtrate
hypotonic to the blood as it enters the distal convoluted
tubule.
The tissues then become more concentrated than the filtrate
which would normally lead to osmosis but water is
prohibited from leaving because of the impermeable walls
of the ascending limb.

The mode of action of the loop of Henle is also called a

countercurrent multiplier system since the filtrate flows in
opposite directions in the two limbs. The pumping of
sodium chloride in the ascending limb and the withdrawal
from water in the descending limb can be multiplied if the
loop is longer and this is important in water conservation as
more water can be withdrawn and a more concentrated
urine produced. This works since the concentration of
solutes in the medulla causes the water in the collecting
duct to exit the filtrate and be reabsorbed into the blood.
DISTAL CONVOLUTED TUBULE
The cells of the wall of the distal convoluted tubule are
similar to those of the proximal convoluted tubule,
having numerous microvilli and mitochondria and
carries out active transport. However, this tubule
reabsorbs varying quantities of inorganic ions in
accordance with the body's needs.
It can also secrete substances into the filtrate to maintain
a particular condition (example: control of pH). The
walls of the distal convoluted tubule are permeable to
water only if the ADH (anti-diuretic hormone),
otherwise, it is impermeable to water. If it is permeable,
water exits the filtrate and enters the bloodstream and
an isotonic filtrate enters the ducts. If it is not
permeable, a hypotonic filtrate enters the collecting
ducts.
THE COLLECTING DUCT
The distal convoluted tubule ends in the collecting
duct. (Several nephrons can share one collecting
duct.) Final modifications are made to the filtrate
which is then emptied into the pelvis of the kideny
as urine.
Like the walls of the distal convoluted tubule, the
walls of the collecting ducts are only permeable to
water if ADH is present, otherwise, it is
impermeable to water.
BASIC RENAL PROCESSES
There are three basic Renal processes:

 Glomerular filtration.

 Tubular reabsorption

 Tubular secretion
BASIC RENAL PROCESS
Urine formation:
 Filtration from of plasma
from the glomerular
capillaries into the
Bowman‟s space.
 Movement from the tubular
lumen to the peritubular
capillaries is the process
called tubular reabsorption
 Movement from the
peritubular capillaries to the
tubular lumen is the process
known as tubular secretion
 Once in the tubule the
substance need not be
excreted , it can be
reabsorbed.
 These processes do not
apply to all substances.
E.g.
- Glucose (completely
reabsorbed.)
- Toxins ( Secreted and not
reabsorbed)
 A specific combination of glomerular filtration ,
tubular reabsorption and tubular secretion applies to
different substances found in the plasma.
 It is important to note that the rates of these processes
are subject to physiological control.
 The rates of these processes will therefore be changed
in order to ensure homeostatic regulation.
 A forth process is also important to some substances,
this is known as metabolism by the tubular cells.
Glomerular Filtration
 The filtration of plasma from the glomerular capillaries into the
Bowman‟s space is termed glomerular filtration.
 The filtrate is termed glomerular filtrate or ultrafiltrate
 Glomerular filtration is a bulk flow process
 Filtrate contains all plasma substances except protein.
Table 1 : Constituents of the Glomerular filtrate
Filtered Not filtered
Low molecular weight Most plasma proteins ie.
substances (including Albumins & Globulins.
smaller peptides)
water Plasma calcium and fatty acids

 Collected in the Bowman‟s space of the Bowman‟s capsule.

 Fenestrations found in the glomerular capillary walls are
not large enough to allow the passage of large proteins
from the plasma, smaller proteins however are allowed to
pass.
 RECALL : Basement membrane is a gelatinous layer
composed of collagen and glycoproteins .
 Glycoproteins in the basement membrane discourage the
filtration of small plasma proteins.
 Glycoproteins are negatively charged and therefore they
repel small molecular weight proteins such as albumin
which is also negatively charged.
 Less than 1 % of albumin molecules escape the Bowman‟s
capsule. Those that do are removed by exocytosis in the
proximal tubule
Forces involved in filtration
Table 2 : Forces involved in the Glomerular filtration
Favouring filtration Opposing filtration

Glomerular capillary blood Fluid pressure in Bowman‟s

pressure space
Osmotic force due to
protein in plasma

- Net glomerular filtration pressure = P GC - P BS - ∏ GC

- Net filtration pressure is normally always positive.
Forces involved
in glomerular
filtration

( Widmaier E. et al,
2008)
RATE OF GLOMERULAR
FILTRATION ( GFR )
 GFR : the volume of fluid filtered from the glomeruli
into the Bowman‟s space per unit time
 Determined by :1. Net filtration pressure
2. Permeability of the corpuscular
membranes
3. Surface area available for filtration
GFR is not fixed but is subject to physiological
regulation , which causes a change in the net filtration
pressure due to neural and hormonal input to the
afferent and efferent arterioles.
Decreased GFR
 Constriction if afferent
arteriole causes a decrease in
hydrostatic pressure in the
glomerular capillaries, this
results in decreased GFR
 Dilation of the efferent
arteriole results in a
reduction in hydrostatic
pressure in the glomerular
capillaries resulting in a
decreased GFR
Increased GFR
 Constriction of the efferent
arteriole results in an
increase in hydrostatic
pressure in the glomerular
capilleries. Results in
increased GFR
 Dilation of afferent arteriole
causes an increase in
hydrostatic pressure in the
glomerular capilleries. This
results in an increase in GFR
Tubular Reabsorption
 Movement of substances from the tubular lumen to the
interstitial fluid does not occur by bulk flow due to
inadequate pressure differences and permeability of the
tubular membranes
 Tubular reabsorption involves the reabsorption of certain
substances out of filtrate by either diffusion or mediated
transport
 Substances are then returned to capillary blood which
surround the kidney tubules.
 Tubular reabsorbtion mainly occurs in the Proximal tubule
and the Loop of Henele
Data for a few
plasma components
that undergo
filtration and
reabsorption .

(Widmaire E. et al ,
2008)
 Diffusion usually occurs across the tight junctions connecting
the epithelial cells
 Mediated transport requires the participation of transport
protiens in the membranes of the tubular cells.

Table 3 : Methods of Tubular reabsorption

Diffusion Mediated Transport

Water reabsorption creates
concentration gradient across
tubular epithelium.
Example: Urea , variety of
lipid soluble organic
substances
Reabsorption coupled with the
reabsorption of sodium.
Requires the use of
transporters.
Example : glucose , amino
acids
Reabsorption by Mediated Transport
 Substances which are reabsorbed by mediated transport
must cross the luminal membrane followed by the
diffusion across the cytosol of the cell and finally across
the basolateral membrane.
 The substance is usually transported across the basolateral
membrane by mediated transport, that is it is usually
coupled with the reabosorption of sodium.
 This occurs via secondary active transport.
Diagramatic
representation of
tubular
epithelium.
(Widmaier E. et al,
2008)
Tubular secretion
 Involves the transport of substances from peritubular capillaries
into the tubular lumen.

 Secretion occurs via diffusion and transcellular mediated

transport.

 Organic anions and cations are taken up by the tubular epithelium

from the blood surrounding the tubules and added to the tubular
fluid.

 Hydrogen ions and potassium are the most important substances

secreted in the tubules.

 Other noteworthy substances secreted are metabolites such as

choline and creatinine and chemicals such as penicillin.
 Active transport is required for the movement of the
substances from the blood to the cell or out of the cell and
into the tubular lumen.
 Usually coupled with the reabsorption of sodium
Metabolism by Tubules
 The cells of the renal tubules synthesize glucose and add
it to the blood.
 Cells also catabolize substances such as peptides which
are taken from the tubular lumen or peritubular capillaries.
 Catabolism eliminates these substances from the body.
REGULATION OF MEMBRANE
CHANNELS
 Tubular reabsorption and secretion of many substances in
the nephrons are subjected to regulation by hormones and
paracrine/ autocrine factors.
 Control of these substances is done by regulating the
activity and the concentrations of the membrane channel
and transporter proteins which are involved.
Division of labour in the tubules
 The primary role of the proximal tubule is to reabsorb most of
the filtered water and filtered plasma solutes after the filtration
in the Bowman‟s capsule.
 Proximal tubule is a major site for solute secretion.
 Henle‟s loop also reabsorbs relatively large quantities of major
ions and to a lesser extent water. It therefore ensures that the
mass of water and solute is smaller as it enters the following
segments of the nephron
 The distal segments determine the final amount of substances
excreted in the urine.
 Homeostatic controls act more on the distal segments of the
tubule.
Renal Clearance
Renal clearance of any substance is the volume of plasma
from which that substance is completely cleared per unit
time.
Clearance of S=mass of S secreted per unit time/ plasma
concentration of S
Any substance filtered ,but not reabsorbed, secreted or
metabolized by the kidneys is equal to the Glomerular
Filtration Rate. How ever no substance completely meets
this criteria and therefore creatinine clearance is used to
approximate the GFR
Generalization that any substance clearance is greater than
GFR that substance undergoes secreation.
Micturition
 Remaining fluid containing excretory substances is
called urine.
 Urine is stored in the bladder and periodically ejected
during urination. This is termed Micturition.
 The bladder is a balloon like chamber with walls of
smooth muscle collectively termed the detrusor
muscle. The contraction of this muscle squeezes on
the urine to produce urination.
Control of Bladder.
Micturition
 Contraction of the external urethral sphincter can prevent
urination
 Contraction of the detrusor muscle causes the internal
urethral sphincter to change shape
 As the bladder fills, stretch receptors are stimulated. The
afferent fibers from these receptors enter the spinal chord
and stimulate the parasympathetic neurons which leads to
the contraction of the detrusor muscle.
 Input from the stretch receptors also inhibits the
sympathetic neurons to the internal urethral sphincter
muscle.
 Descending pathways from the brain can influence
this reflex.
 These pathways stimulate both sympathetic and
somatic motor nerves therefore preventing urination.
Table 3 : Sources of water gain and loss in the body

Water Gain in the Body Water loss in the body

Ingested in liquids and food Skin
Produced from oxidation of Respiratory Airways
organic nutrients

Gastrointestinal Tract
Urinary Tract
Menstrual Flow
Fig : Average Daily Water Gain and Loss in
Adults
( Widmaier E. , 2008)
 Water loss from skin and lining of respiratory tract is
known as insensible water loss
 Water loss from gastrointestinal tract can be made severe
in diarrhoea.
 Small quantities of Sodium and Chloride are excreted
from skin and gastrointestinal tract.
 During severe sweating , diarrhoea ,vomiting and
hemorrhage increased amounts of sodium and chloride are
excreted.
Fig: Daily Sodium Chloride Intake and Loss
(Widmaier , E. , 2008)
 From Figure 1 and 2 it is seen that salt and water losses
equal salt and water gains.
 This is as a result of regulation of urinary loss.
 Healthy normal kidneys can readily alter the excretion of
salt and water to ensure loss is balanced with gain
 Sodium and water are filtered from the glomerular
capillaries and into the Bowman‟s space

 As a result of the low molecular weights of Sodium and

water and how they are circulated in the plasma in their
free form
 Reabsorption occurs in the proximal tubule

 Major hormonal control of reabsorption occurs in the

DCT and CD

 The mechanism of Sodium reabsorption is an

ACTIVE process which occurs in all tubular segments
but not in the descending limb of the loop of Henle

 Water reabsorption occurs through diffusion but is

highly dependant on Sodium reabsorption
Primary Active Transport of Sodium
 Sodium is removed from the cell and into the interstital
fluid via Primary Active Transport via the Sodium and
Potassium ATPase pumps located in the basolateral
memebrane.

 Intracellular conc of Na to be lower than in the tubular

lumen
 There is downhill movement of Na out of the
lumen and into the tubular epithelial cells

 Varies from segment to segment in the tubule depending on

the channels or transport proteins found in the luminal
membrane

 In the basolateral membrane step the active transport process

lowers intracellular Na conc thus allows for the downhill
luminal entry step
 In the proximal tubule luminal entry occurs via cotransport
molecules like glucose while countertransport with
hydrogen ions

 Reabsorption of cotransport molecules and secrection of

hydrogen ions are driven by Na reabsorption.

 In the CCD sodium enters from the tubular lumen and into
the cell via diffusion through sodium channels
Coupling of Water Reabsorption to
Sodium Reabsorption
 Sodium is transported from the tubular lumen to the
intersitial fluid across the epithelial cells

 The removal of solutes from the tubular lumen local

osmolarity of tubular fluid adjacent to the cell
*while the removal of solutes from the interstital fluid
outside of the cell local osmolarity
 Difference in water conc between the lumen and interstital
fluid causes a net diffusion of water from the lumen across
the tubular cells or the tight junctions and into the interstital
fluid

 Water, Na and other solutes are dissolved in the interstital

fluid and move into the peritubular capillaries by bulk flow-
Final step of reabsorption
 Aquaporins are integral porin proteins found on the
plasma membrane of the tubular epithelium commonly
known as water channels.

 Movement of water depends on the permeability of the

epithelium.

 The proximal tubule has a high water permeability hence

it reabsorbs water at a similar rate to sodium ions
Critical- Water permability
varies in the cortical and the
medullary collectingf ducts due
to physiogical control
 (discussed later on)
Vasopressin/ Antidiuretic Hormone
(ADH)
 Stimulates the insertion into the luminal membrane of
certain aquaporin water channels by exocytosis

 As plasma conc increases water permeability of the CD

becomes greater

 Water diuresis occurs when there are low levels of the

hormone. Little water is reabsorbed and is excreted in the
urine
 Diabetes Insipidus- Occurs as there is a deficiency of or
the kidney‟s inability to respond ADH

 Signs and Symptoms:

Excessive Thirst, Excretion of large amounts of severely
diluted urine, Blurred Vision and Dehyration

Osmotic diuresis- Increased urine flow results from the

increase in solute excretion.
Urine Concentration: The
Countercurrent Multiplier System
 Obligatory water loss- The minimal amount of fluid loss
from the body which can occur.

 Takes place as tubular fluid flows through the medullary

CDs

 ADH causes water to diffuse out of MCD and into the

interstital fluid of the medulla to be carried by the blood
vessels.
How does medullary fluid become
hyperosmotic?
 The countercurrent anatomy of the loop of Henle of
juxtamedullary nephrons
 Reabsorption of NaCl in the ascending limb of those loops
of Henle
 Impermeablilty of those ascending limbs to water
 Trapping of urea in the medulla
 Hairpin loops of vasa recta to minimize wash out of the
hyperosmotic medulla
Ascending limb:
 In the ascending limb Sodium and Chloride are
reabsorbed from the lumen to the medullary interstitial
fluid

 The upper thick area reabsorption occurs via transporters

which actively transports sodium and chloride. It is a
passive process

 It is imperable to water therefore resulting in the

interstitial fluid of the medullary to be hyperosmmotic to
that of the fluid in the ascending limb
 Descending limb
 Diffusion of water occurs from the descending limb and
into the interstital fluid

 The fluid hyperosmolarity is maintained by the ascending

limb

 The loop of Henle countercurrent multipler- Causes

interstitial fluid of the medulla to become concentrated
hence water will draw out from the collecting ducts and
thus concentrates the urine with solutes.
 Osmolarity increases as tubular fluid goes deeper into the
medulla.

 NB: Active Sodium Chloride transport mechanism in the

ascending limb is an essential component to the system
because without it the countercurrent flow would have no
effect on the loop and its medullary interstitial osmolarity
 In the DCT the fluid becomes more hyperosmotic
because it actively transports sodium and chloride out of
the tubule and is reletaviely imperable to water. Fluid
now enters CCD

 High levels of Vasopressin causes water reabsorption

to occur by diffusion from the hyperosmotic fluid in
CCD until the fluid becomes isoosmotic to the
interstitial fluid and peritubular plasma of the cortex

 Along the lengths of the MCD water diffuses out of the

collecting ducts and into the interstitial fluid.
 The water which is reabsorbed enters the medullary
capillaries and is carried out of the kidneys via the
venous blood.

 Final urine is hyperosmotic

 When plasma ADH is low the CCD and MCD are

imperable to water thus resulting in a large volume of
hypoosmotic urine is excreted which would remove
excess water in the body
Medullary Circulation
 Blood Vessels(Vasa recta) in the medulla form hairpin
loops which run in a parallel position to the loops of Henle
and MCD

 Blood enters the vessel loop and flows down deeper and
deeper while sodium and chloride diffuse into the blood
while water diffuses out

 Bulk Flow- maintains the steady state countercurrent

gradient set up by the loops of Henle
Recycling of Urea

 Urea is reabsorbed and secreted into the tubule and then

reabsorbed again

 Urea is then trapped in the medullary interstitium hence

increasing its osmolarity

 Half of the urea is reabsorbed in the proximal tubule and

the remainder enters the loop of Henle

 Urea is secreted back into the tubular lumen via facilitated

diffusion
 Urea is reabsorbed from the distal tubule and the CCD

 Half of the urea is then reabsorbed from the MCD and 5%

in the vasa recta

 The remainder is secreted into the loop of Henle

 NB: Only 15% of the urea which was filtered remains

in the Collecting Duct and the remaining excreted as
urine
 Renal Regulation of pH

An important function of kidney is to regulate the function

by excreting either acidic [H+] or basic [OH-] urine.
The pH of urine ranges from 4.5 to 9.5, because the renal
system plays a significant role in long term pH
maintenance of the blood at 7.4 0.05.
This is possible by its capacity of reabsorption, secretion
and excretion of the non-volatile acids like lactic acid,
pyruvic acid, HCl, phosphoric acid and H2SO4 which are
produced in the body cannot be excreted by lungs.
The first mechanism for removal of acids (H+) from the
body is by renal excretion.
Regulation of H+ Ions
 Regulation of H+ Through
Ammonia
 The kidney is to buffer acids and
thus to conserve fixed base
through the production of NH3
from amino acids with the help
of an enzyme glutaminase.
 Whenever there is excess acid
production the NH3 production
is also which combines with
H+ to form NH4+ which is
excreted as NH4Cl. This occurs
in the event of acidosis. When
alkali is in excess, the H+ is
reabsorbed into the cell in
exchange to Na+/K+.
 Regulation of H+ Through
Bicarbonate System
 The filtered HCO3– combined
with H+ H2CO3, carbonic
anhydrase present in the brush
border of the cell wall dissociate
H2CO3 H2O + CO2.
 The CO2 diffuses into the cell.
The CO2 combines with H2O to
form H2CO3 again. This H2CO3
again ionizes to HCO3– + H+
with the help of carbonic
anhydrase of acid-base balance.
 Regulation of H+ Through
Bicarbonate System
 The H+ diffuses into the
lumen in exchange for
Na+ and HCO3– is
reabsorbed into plasma
along with Na+.
 There is no net
excretion of H+ or
generation of new
HCO3– . So this
mechanism helps to
maintain a steady state
 Calcium and phosphate are controlled mainly by
parathyroid hormone.
 The parathyroid hormone (PTH) is a protein hormone
produced in the parathyroid glands.
 The PTH controls the kidneys.
 A decline in plasma calcium concentration causes PTH to
be secreted and an increase in plasma calcium
concentration does the opposite.
 The kidney filters 60% of plasma calcium.
 Calcium is essential for the functioning of the majority of
the body‟s functions
 Therefore the kidney reabsorbs calcium from tubular fluid.
 More than 60% of calcium reabsorption occurs in the
proximal tubule and is not under the control of any
hormones.
 The distal convoluted tubule and in the beginning of
cortical collecting duct are mainly involved in the
hormonal control of calcium reabsorption.
 PTH stimulates calcium channels to open.
 This causes an increase in calcium reabsorption.
 PTH increases 1-hydroxylase enzyme activity which in
turn stimulates 25(OH)-D to 1,25 (OH)2 D.
 This causes an increase in calcium and phosphate
absorption in the gastrointestinal tract.
 The majority if the phosphate that is filtered is reabsorbed
in the proximal tubule.
 Conversely PTH decreases phosphate reabsorption
 Thus the excretion of phosphate is increased.
 In conclusion when the plasma calcium concentration
declines and PTH and calcium reabsorption increases, the
excretion of phosphate is increased.
HORMONES AND THE
KIDNEY
 Renin increases the production of angiotensin II
which is released when there is a fall in intravascular
volume e.g haemorrhage and dehydration. This leads
to:
 Constriction of the efferent arteriole to maintain GFR, by
increasing the filtration pressure in the glomerulus.
 Release of aldosterone from the adrenal cortex
 Increased release of ADH from the posterior pituitary
 Thirst
 Inotropic myocardial stimulation and systemic arterial
constriction
 The opposite occurs when fluid overload occurs.
HORMONES AND THE
KIDNEY
(cont’d)

 Aldosterone (secreted by the adrenal gland) promotes

sodium ion and water reabsorption in the distal tubule and
collecting duct where Na+ is exchanged for potassium
(K+) and hydrogen ions by a specific cellular pump.
 It is also released when there is a decrease in serum
sodium ion concentration.
 E.g. This can occur, when there are large losses of gastric
juice. Gastric juice contains significant concentrations of
sodium, chloride, hydrogen and potassium ions. Therefore it
is impossible to correct the resulting alkalosis and
hypokalaemia without first replacing the sodium ions using
0.9% saline solutions.
HORMONES AND THE KIDNEY
(cont’d)

 Atrial Natruretic Peptide(ANP) is released when atrial

pressure is increased e.g. in heart failure or fluid overload. It
promotes loss of sodium and chloride ions and water chiefly by
increasing GFR.
 Antidiuretic Hormone (ADH or vasopressin) is synthesized
by the cells in the supraoptic and paraventricular nuclei of the
hypothalmus, transported along a neural pathway (i.e.,
hypothalamohypophysial tract) to the neurohypophysis (i.e.,
posterior pituitary); and then released into the circulation.
 It increases the water permeability of the distal tubule and
collecting duct, thus increasing the concentration of urine.
 In contrast, when secretion of ADH is inhibited, it allows dilute
urine to be formed. This occurs mainly when plasma sodium
concentration falls such as following drinking large quantities of
water. This fall is detected by the osmoreceptors.
HORMONES AND THE KIDNEY
(cont‟d)

 Stretch receptors
(baroreceptors) that are
sensitive to changes in blood
pressure and central blood
volume aid in the regulation
of ADH release.
 The hormones interact when
blood loss or dehydration
occurs to maintain
intravascular volume.
FIGURE 20
FIGURE 21
Sodium Regulation
 The kidney monitors arterial pressure and retains sodium
when the arterial pressure is decreased and eliminates it
when the arterial pressure is increased
 Sodium reabsorption is an active process occurring in all
tubular segments except the descending limb of the loop
of Henle.
 Water reabsorption is by diffusion and is dependent upon
sodium reabsorption.
 The primary mechanism driving all transport in the
proximal tubule is the Na-K ATPhase mechanism located
on the basolateral membrane of the tubular cells.
Sodium Regulation(cont’d)
 The rate at which the kidney excretes or conserves sodium
is coordinated by the sympathetic nervous system and the
renin-angiotensin-aldosterone system.
 When Na + concentration falls, blood pressure and volume
falls because water is lost with the Na +.
 The fall in blood pressure causes renin to be released into
the bloodstream where it catalyses the conversion of the
plasma proteins into angiotensin.
 The angiotensin stimulates the adrenal cortex to secrete
aldosterone.
 Reabsorption of Na + is accompanied by the loss of K +
(Na + - K + balance).
Sodium Regulation
(cont’d)
 The sympathetic nervous system responds to changes in
arterial pressure and blood volume by adjusting the GFR
and the rate at which sodium is filtered from the blood.
 Sympathetic activity also regulates tubular reabsorption of
sodium and renin release.
 The reninangiotensin- aldosterone system exerts its
action through angiotensin II and aldosterone .
 Angiotensin II acts directly on the renal tubules to increase
sodium reabsorption. It also acts to constrict renal blood
vessels, thereby decreasing the glomerular filtration rate
and slowing renal blood flow so that less sodium is filtered
and more is reabsorbed. Angiotensin II is also a powerful
regulator of aldosterone, a hormone secreted by the adrenal
cortex.
FIGURE 22
Sodium Regulation(cont’d)
 Aldosterone acts at the level of the cortical collecting
tubules of the kidneys to increase sodium reabsorption
while increasing potassium elimination.
 It increases the uptake of Na by the and reabsorption in
the kidneys which causes the concentration of Na+ in the
blood to rise. This method of control depends on a
feedback.
 If the concentrations of Na + is too high, the adrenal
cortex becomes inhibited and secretes less aldosterone
and vice verse.
 Feedback involves the co-factor renin which is released in
the afferent glomerular arerioles.
Sodium Regulation(cont’d)
 Na + is transported out of the cell into the paracellular
space and K + into the cell.
 This reduces the cell Na + concen. and the raises the K +
concen.
 This causes a concentration gradient in which the presence
of K conductance renders the cell electrically negative wrt
its surroundings.
 In a steady state the pump operates below saturation point
for Na + and an increase in Na + entry across the apical
membrane increases the pump rate.
 The proximal tubule sodium reabsorption drives the
reabsorption of the cotransported substances (glucose and
the secretion of hydrogen ions.
Renal water regulation
 Water excretion is the difference between the volume
 of water filtered (the GFR) and the volume reabsorbed
 Two mechanisms which assist in the regulation of body
water are: thirst and antidiuretic hormone (ADH).
 Thirst is the primary regulator of water intake and ADH is
a regulator of water output. The both respond to changes
in extracellular osmolarity and volume.
 Thirst is an emergency response which is controlled by the
hypothlamus. An important stimulus for thirst is
angiotensin II, which becomes increased in response to
low blood volume and low blood pressure.
 ADH acts throught two receptors (V1) and (V2) of which
the (V2) are located on the tubular cells of the cortical
collecting duct.
Renal water regulation (cont’d)
 They control water reabsorption by the kidneys.
 ADH binds to the V2 receptors which increase the
permeability of the collecting duct to water (antidiuretic
effect). The receptor is coupled via a GTP-requiring
stimulatory protein (Gs protein) to the enzyme adenylyl
cyclase.
 The enzyme stimulates the production of cyclic AMP
which activates protein kinase A. This kinase induces the
insertion (exocytosis) of water channels, aquaporin 2.
Aquaporin 2 (from the V2 receptors) move from the
cytoplasm of the cells of the collecting duct to the huminal
surface of these cells.
Renal water regulation (cont’d)
 Aquaporins 3 and 4 form the water channels in the
basolateral membrane of the principal cells. These are not
regulated by ADH (they are constitutively active).
 These channels then allow free movement of water from
the tubular lumen into the cells along a concentration
gradient.
 When ADH is not stimulated, the aquaporin 2 channels
readily move out f the apical membrane so that water is no
longer transferred out of the collecting duct.
 Without ADH, the permeability of the collecting duct to
water is very low; this results in polyuria.
 The mechanism of action of ADH on principle cells, V2=
vasopressin2 receptor, AQ2= aquaporin 2
Potassium Regulation
 Increases or decreases in extracellular potassium
concentration can cause abnormal rhythms of the
heart (arrhythmias) and abnormalities of skeletal-
muscle contraction.
 Potassium levels are largely regulated by renal
mechanisms that conserve or eliminate potassium.
 Major route for elimination is the kidney.
 Regulation is controlled by secretion from the blood
into the tubular filtrate rather than vice versa.
Potassium Regulation (cont’d)
 Potassium is filtered in the glomerulus, reabsorbed
along with sodium and water in the proximal
tubule and with sodium and chloride in the thick
ascending loop of Henle, and then secreted into
the late distal and cortical collecting tubules for
elimination in the urine.
 Aldosterone plays an essential role in regulating
potassium elimination by the kidney. In the presence
of aldosterone, sodium is transported back into the
blood and potassium is secreted into the tubular
filtrate for elimination in the urine (N+- K+ shift).
Potassium Regulation (cont’d)
 When body potassium is increased, extracellular potassium
concentration increases. This increase acts directly on the
cortical collecting ducts to increase potassium secretion and
also stimulates aldosterone secretion, the increased plasma
aldosterone then also stimulating potassium secretion.
 There is also a (K+- H+)exchange system in the collecting
tubules of the kidney. When serum potassium levels are
increased, potassium is secreted into the urine and hydrogen is
reabsorbed into the blood, producing a decrease in pH and
metabolic acidosis. Conversely, when potassium levels are low,
potassium is reabsorbed and hydrogen is secreted into the
urine, leading to metabolic alkalosis.
Bibliography
 cikgurozaini.blogspot.com
 apbrwww5.apsu.edu
 http://www.nda.ox.ac.uk/wfsa/html/u09/u09_017.htm
Outline
 What are diuretics?
 How do they work and what are some examples of
diuretics?
 What are some clinical situations in which diuretics are
used?
Diuretics
 These are agents which increase the mobilization of extra
cellular fluid(ECF) this usually involves the loss of ions
and water

 Diuretics are drugs that are utilized clinically to increase

the volume of urine excretion.
Diuretics
1. Loop diruetics
 Example: eg Furosemide( Lasix)
 Loop diuretics act on the ascending limb of the Loop of
Henle, it inhibits the transport of protein which mediates
the first step in sodium reabsorption.
Diuretics
1. Loop diruetics eg furosemide( Lasix)
Diuretics
2. Potassium sparing agents

 There are two types

 Aldosternone Antagonist (i.e. block action
of aldoesterone)
 Na channel inhibtor {i.e. block the
epithelial sodium channel (in the cortical
collecting duct)
Diuretics
Diuretics
 There are many clinical situations in which the use of
diuretic therapy can provide advantageous

 These include
 Heart Failure with Edema
 Hypertension
Diuretics
Heart Failure with Edema
 Decrease cardiac output causes the kidney to
respond as if there is decreased blood volume
 Retention of more salt and water
 Increase in blood volume to heart
 increase vascular volume resulting in edema

 Loop diuretics are use to reduce the volume

Diuretics
Hypertension.
 Hypertension (usually too much salt)

 Diuretic-induced excretion decreases Na+ and H2O in the

body, which results in
 Reduce blood volume which reduces the blood pressure
 arteriolar dilation and further more lowers the pressure of
the blood.
Kidney diseases
 There are many types of diseases that can affects the
kidney
 These can be divided into
 Congenital
 Acquired
 allergies,
 bacteria,
 tumors,
 toxic chemicals
 kidney stones (accumulation of mineral deposits
in nephron tubules).
Kidney diseases
 Kidney disease can also be classified as
 Acute
 Low blood volume
 Exposure to kidney toxic substances
 Obstruction of urinary tract

 Chronic
 Diabetes
 Hypertension

 Glomeruloneprhritis ( inflammation of glomeruli )

Acute kidney injury
 Pre renal
 Usually caused by decreased blood flow to the kidney
 Intrinsic
 Damage to the kidney itself predominantly affecting the
glomerulus or tubule
 Post renal
 Usually occurs due to urinary tract obstruction
Acute kidney injury
Signs
 There will be decrease in urine output.
 Substances normally eliminated by the kidney tend to
increase
 Urea
 Creatine
 Sodium and potassium, electrolytes that are commonly
deranged due to impaired excretion and re absorption
Chronic Kidney disease
 There are approximately 1 million nephrons are present in
each kidney,. The summation of all the nephrons
contribute to the Glomerular filtration Rate(GFR)

 The kidney has the ability when renal injury occurs, the
GFR is maintained

 This is ability allows the clearance of harmful substance to

continue largely unaffected till the GFR has decreased to
50 percent of it normal value.
Chronic Kidney disease
Causes include:

 Vascular disease
 Hypertension

 Glomerular disease (primary or secondary)

 Diabetes mellitus

 Tubulointerstitial disease
 Drugs (eg, sulfa, allopurinol)

 Urinary tract obstruction

 Tumors
Chronic Kidney disease
 Clinical problems associated with chronic kidney disease
include
 Hyperkalemia
 Metabolic acidosis
 Anemia
 Bone disease
Chronic Kidney disease
Hyperkalemia

 The ability to maintain potassium (K) excretion at near-normal

levels is generally maintained in chronic kidney disease.

 However when the GFR falls to less than 20-25 mL/min there
is decreased ability of the kidneys to excrete potassium.

 Resulting in Hyperkalemia
Chronic Kidney disease
Salt and water handling abnormalities
 As kidney function declines, there is excessive sodium
retention which will cause extracellular volume
expansion leading to peripheral edema
Kidney Disease
Chronic
Anemia
Kidney disease
 This develops from decreased renal synthesis of
erythropoietin, the hormone responsible for bone marrow
stimulation for red blood cell (RBC) production.
Chronic Kidney disease
Chronic Kidney disease
Bone disease
 Renal bone disease is a common complication of chronic
kidney disease.
 Decreased renal synthesis of 1,25-
dihydroxycholecalciferol (calcitriol)
 Hypocalcaemia develops primarily from decreased
intestinal calcium absorption because of low plasma
calcitriol levels
Kidney Disease
Kidney Disease
References:
Vander‟s Human Physiology 10th Edition, Eric P. Widmaier, Hersel Raff, Kevin T. Strang
http://emedicine.medscape.com/article/238798-overview#a0104
http://en.wikipedia.org/wiki/File:Gray1128.png
http://kidney.niddk.nih.gov/kudiseases/pubs/proteinuria/

http://3.bp.blogspot.com/_kaQ5P19FVgk/SwWAH4PM9kI/AAAAAAAAETw/hkXpMi1NQGQ/s
400/ProximalConvolutedTubule.JPG
http://www.google.tt/imgres?q=cortical+collecting+duct&hl=en&rlz=1C1_____en-
GBTT437TT437&biw=1024&bih=456&tbm=isch&tbnid=8V5ptLll587HQM:&imgrefurl=http://o
pen.jorum.ac.uk/xmlui/bitstream/handle/123456789/947/Items/S324_1_section8.html&docid=Fpt
ccfGU81hJJM&w=510&h=588&ei=W3R6TsXKI8Xc0QGH1byoAg&zoom=1&iact=hc&vpx=67
0&vpy=111&dur=944&hovh=239&hovw=208&tx=113&ty=155&page=1&tbnh=115&tbnw=100
&start=0&ndsp=11&ved=1t:429,r:9,s:0
 http://www.google.tt/imgres?q=proximal+tubule+cells&hl=en&sa=X&rlz=1C1_____en-
GBTT437TT437&biw=1024&bih=499&tbm=isch&prmd=imvns&tbnid=eKM4E-
R07hFL1M:&imgrefurl=http://www.uic.edu/classes/bios/bios100/lecturesf04am/lect21.htm&doci
d=1qQumxeqTWij_M&w=360&h=440&ei=q_p8TqijIafj0QHm7-
znDw&zoom=1&iact=hc&vpx=106&vpy=139&dur=1451&hovh=248&hovw=203&tx=113&ty=
189&page=1&tbnh=144&tbnw=118&start=0&ndsp=8&ved=1t:429,r:4,s:0
Kidney Disease
 http://www.google.tt/imgres?q=renal+corpuscle+diagram&hl=en&rlz=1C1_____en-
GBTT437TT437&biw=1024&bih=456&tbm=isch&tbnid=9gXIjDjjaMJvqM:&imgrefurl
=http://www.profelis.org/webpages-
cn/lectures/urinary_physiology.html&docid=0v09nrgwAWVXNM&w=707&h=515&ei=
YPt8TtvxMKTv0gHF-
LDaDw&zoom=1&iact=hc&vpx=91&vpy=167&dur=109&hovh=192&hovw=263&tx=1
27&ty=199&page=1&tbnh=120&tbnw=165&start=0&ndsp=11&ved=1t:429,r:5,s:0
 http://www.google.tt/imgres?q=renal+corpuscle+diagram&hl=en&rlz=1C1_____en-
GBTT437TT437&biw=1024&bih=456&tbm=isch&tbnid=boI10CF6dX0OVM:&imgref
url=http://apbrwww5.apsu.edu/thompsonj/Anatomy%2520%26%2520Physiology/2020/2
020%2520Exam%2520Reviews/Exam%25204/CH25%2520Nephron%2520I%2520-
%2520Renal%2520Corpuscle.htm&docid=RdYeUelnc4_AbM&w=699&h=383&ei=YPt
8TtvxMKTv0gHF-
LDaDw&zoom=1&iact=hc&vpx=77&vpy=144&dur=94&hovh=166&hovw=303&tx=18
2&ty=95&page=1&tbnh=97&tbnw=177&start=0&ndsp=11&ved=1t:429,r:0,s:0
DIABETES MELLITUS
 A common cause of renal failure is uncontrolled diabetes
mellitus
 Diabetes meaning “running through” denotes increased urinary
volume excreted by the persons suffering with this disease.
 Diabetes can be due to:
1. Deficiency of insulin
2. Decreased responsiveness to insulin
 This abnormality in carbohydrate metabolism leads to high
levels of blood glucose which can lead to considerable damage
to many parts of the body.
 These include kidneys, heart ,eyes and blood vessels.
How does Diabetes affect the
Kidneys
 Recall : 1. Osmotic diuresis , this is the increased urine
flow as a result of a primary increase in the solute
excretion.
2. Glucose is reabsorped by the proximal tubule
via sodium- glucose transport proteins.
 The increase in blood glucose causes an increase in the
rate filtration.
 This increase in rate of filtration causes increased amounts
of protein to be filtered across the glomerular membranes.
 Small amounts of protein eventually appear in the urine.
 The filtered protein leads to increased damage to the
membranes of the renal corpuscle .
How does Diabetes affect the
Kidneys
 As the kidneys become more compromised larger
amounts of protein is allowed to pass from the blood
and be excreted in the urine. Leads to proteinuria
 Kidney function begins to deteriorate.
 Irreversible damage to the kidneys leads to toxic
waste not being able to be filtered out of blood and
dialysis is required.
 This is the usual course of diabetic necropathy which
results in end stage kidney disease.
How Diabetes affect the Kidneys
 Diabetic necropathy is the disease of the capillaries in
the kidney glomeruli. That is they show
glomerulosclerosis , which is the hardening of the of
the glomerulus of the kidney due to scarring.
 Diabetic necropathy is progressive and results in death
2 – 3 years after diagnosis. It is also the leading cause
of premature death in young diabetics.
How does Diabetes affect the
Kidneys
 When the blood sugar level of a person rises the
glucose is detected in the urine.
 That is there is an increased glucose load in the
proximal tubule. Some glucose therefore escapes
reaborption and causes a retention of water in the
lumen.
 This water is excreted along with the glucose.
 Persons with diabetes usually excrete large amounts
of urine.
Diabetes insipidus
 Diabetes insipidus is caused by the failure of the posterior
pituitary to release the hormone vasopressin or the
inability of the kidney to respond to vasopressin.
 RECALL: Water reabsorption in the last portions of the
tubules and coritcal collecting ducts can vary greatly due
to physiological control. The major control is the peptide
hormone vasopressin or antiduretic hormone (ADH)
- [vasopressin] results in an in water permeability
- [vasopressin] results in an in water permeability
 In patients with diabetes insipidus the kidneys are
therefore unable to conserve water
Diabetes insipidus
 Therefore large quantities of dilute urine is produced.
 Persons who have diabetes insipidus will consume
more water
 May also suffer from dehydration
Kidney Stones

Kidney stones may form in the pelvis or calyces of the kidney

or in the ureter.
Kidney Stones
 A kidney stone is an accumulation of mineral deposits
in the nephron.
 Kidney stones may also be due to an infection
 Stones can be calcium, struvite, uric acid or cystine .
 Calcium stones are the most common type. Calcium
which is not used by the bones or muscles goes to the
kidneys.
 Extra calcium is usually removed by the kidneys with
the rest of the urine. Persons therefore with calcium
stones keep the extra calcium in their kidneys.
 The acidity or alkalinity of the urine also affects the
ability of stone forming substances to remain
dissolved.
Kidney Stones
Extracorporeal shock
wave lithotripsy
(ESWL) is a procedure
used to shatter simple
stones in the kidney or
upper urinary tract.
Hyperaldosteronism
 Emcompasses a number of different chronic diseases
all of which involve excess adrenal hormone
aldosterone.
 Conn‟s syndrome – growth of the zona glomerulosa of
the adrenal gland , these tumors release aldosterone in
the absence of stimulation by angiotensin II
 RECALL: Aldosterone is released by the adrenal
cortex which stimulates the sodium reabsorption by
the distal convoluted tubule and the cortical collecting
ducts.
- High [ aldosterone] increased sodium reabsorption
- Low [ aldosterone] deareased sodium reabsorption
( 2% sodium lost in urine)
 In Conn‟s syndrome, there are high levels of aldesterone ,
which leads to an increase in sodium absorption in the
nephron and potassium excretion
 Leads to an increase in blood pressure, due to increased
blood volume which leads to hypertension.
 Renin release is greatly reduced.
 This is one of the most common causes of endocrine
hypertension
 Endocrine hypertension is a secondary type of
hypertension which is usually due to a hormone
imbalance.
Hypokalemia
 This is a lower than normal amount of potassium in the
blood.
 Potassium is obtained from food and is required by the
body for proper nerve function
 Changes in the potassium level therefore can cause
abnormal rhythms in the heart and in the skeletal muscle
contraction
 Recall: Due to an increase in plasma aldosterone there is
an increase in sodium reabsorption and potassium
secretion.
 Hypokalemia is espcially seen in patients with Conn‟s
syndrome
Decrease in Plasma Increase in Plasma
volume Potassium

Increase plasma
angiotensin II

Adrenal cortex
Increase aldosterone secretion

Increase plasma
aldosterone

Cortical collecting ducts

Increased Na + Increased
K+
reabsorption secretion

Increased
Decreased sodium Potassium
excretion excretion
Hypertension
 Commonly known as high blood pressure.
 Normal blood pressure should be 120/80, any
persons with a systolic pressure over 140 or a
diastolic pressure over 90 is considered to have high
blood pressure.
How does hypertension affect the
kidneys
 Hypertension causes an
increase in the work done
by the heart.
 Over time blood vessels in
the body become
damaged.
 The damage of the blood
vessels of the kidney will
lead to the deterioration of
kidney function, that is
they stop removing waste
and extra fluid.
How does hypertension affect the
kidneys
 The extra fluid in the fluid in the blood vessels may further
raise the blood pressure , resulting in a dangerous cycle.
 High blood pressure is one of the leading causes of kidney
failure, also known as end stage renal disease.
References
 http://www.froedtert.com/SpecialtyAreas/Endocrinology/P
rogramsandDiseaseTreatment/EndocrineHypertension.htm
 http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001493/
 http://ehealthmd.com/content/how-do-kidney-stones-form
 http://www.biotecnika.org/blog/vishtiw/diabetes-mellitus-
and-its-effect-kidney-and-liver