Kidneys
Functions
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Regulation of extracellular fluid volume
Removal of nitrogenous waste products, such as ammonia, urea, uric acid, and
creatinine
o Organisms that have access to a lot of fresh water will tend to excrete
ammonia, because this byproduct takes the least amount of energy for
conversion. Ammonia is very toxic to the system and requires a lot of
dilution.
o Urea is an intermediate which is not nearly as toxic as ammonia.
o Uric acid is the least soluble of the nitrogenous products. Organisms that
have little access to water usually metabolize their nitrogenous waste
products as uric acid, because it can be excreted with minimal loss of
water (i.e. birds).
o Creatinine is the breakdown product of creatine (an important energy
transfer molecule in skeletal muscle fibers transferring energy from the
mitochondria to the myosin head). This is present in very stable amounts
in our blood and can be used as an indicator of kidney function. If
creatinine concentration in the blood is increased, it is an indication of a
decline in kidney function.
Removal of organic waste molecules from the blood stream
Regulation of electrolytes
Regulation of pH
Synthesis of the hormone erythropoietin which stimulates RBC production
Synthesis of Vitamin D, influencing calcium balance.
Gluconeogenesis. During prolonged fasting, the kidneys synthesize glucose from
amino acids and other precursors and release it into the blood.
The function of the kidneys relies on having a great deal of blood flow through it in order
to remove wastes and perform all of its functions. The kidney functions best at around
21-25 years of age. At age 70, the average patient has about 50% of the original kidney
function. Problems related to the kidney generally affect four organs: the eye, synovial
joints, kidney, and skin. It is important to remember that whatever pathology is seen in
the eye is also occurring in the kidney.
Anatomy
The Kidney
 There are two kidneys (lima bean shaped, slightly reddish brown in color), one on
each side of the spinal column. They are retroperitoneal, located between the
peritoneum (connective tissue layer lining the abdominal cavity) and the body
wall. They are around the level of the last thoracic and first lumbar vertebrae. The
left kidney is usually placed slightly higher than the right.
 Dimensions: 11.25 cm (h) x 7.5 (w) x 2.5 (t)
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Capsular structures
o There are three tough, thin fibroconnective tissues surrounding the kidney.
o The renal capsule is the innermost layer closest to the kidney, consisting
of fibrous connective tissue. It protects the kidney from infection.
o The adipose capsule is the middle layer that helps in position
maintenance, as well as serving as a buffer to trauma.
o The renal fascia is the outermost layer consisting of dense, fibrous
connective tissue. It surrounds the adrenal gland and anchors the kidneys
to the surrounding structures.
There are three distinct regions of the kidney
o Cortex
 This is the outer region. It is light in color and granular in
appearance. It contains the majority of the nephronal structures.
o Medulla
 This is deep to the cortex and is reddish brown in color. It contains
the cone-shaped renal pyramids with the base of the pyramid
facing the cortex and the papilla (apex) facing the medulla. They
are made of parallel bundles of microscopic tubules, giving it a
striated appearance. The renal columns separate the pyramids.
 Renal papillae are at the apex of the renal pyramids and open into
the internal portion, otherwise known as the renal pelvis
 This region contains portions of the loop of Henle.
o Pelvis
 This is a flat, funnel shaped tube that is continuous with the ureter.
Branching from the renal pelvis forms the major calyces which
branch further to form the minor calyces that enclose the papillae
of the pyramids.
 The calyces collect urine from the papillae and empty urine into
the renal pelvis. Urine flows out the renal pelvis into the ureter,
which is then emptied and stored in the urinary bladder. The walls
of the renal pelvis contain smooth muscle, which transports urine
to the bladder via peristalsis.
Hilus
o This is the depression on the medial aspect of the kidney, through which
blood vessels enter and leave, and from which the ureter leaves.
Blood Supply
o Each renal artery arises from the abdominal aorta and divides into the
interlobar arteries which give rise to the arcuate arteries. These arch over
the base of the meduallary pyramids at the junction of the medulla and
cortex and give rise to cortical radial arteries, which travel toward the
surface of the cortex and supply the afferent arterioles. Each afferent
arteriole leads to a glomerulus.
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Renal Portal System
o The renal portal system contains two capillary beds in series that supply
the nephron. The efferent arteriole, emerging from the glomerulus (first
capillary bed), gives rise to the peritubular plexus (second capillary bed).
 The glomerulus (a high pressure bed) is a tuft of capillaries that
receive blood through an afferent arteriole. This is the only
capillary in the body drained by arterioles rather than venules.
 The group of peritubular capillaries (a low pressure bed) in the
medulla is known as the vasa recta. They surround the nephron
tubule and converge into the renal vein. Fluid filters out of the
tubule and is absorbed into the peritubular capillaries via the
efferent arteriole. This recaptures what was lost from the
glomerulus.
 The glomerulus is separated from the peritubular capillary bed by
the efferent arteriole which offers considerable resistance to blood
flow. Therefore, the glomerular capillary bed is a high pressure bed
while the peritubular capillary bed is a low pressure bed. The
capillaries are low pressure to promote absorption into the blood.
 Note that this is not a normal pattern of blood vessels in the body.
Normally blood flow is
 Arteriole  Capillary  Venule  Vein  Heart.
Blood flow to the nephron has a different pattern.
 Artery  Arteriole  Capillary  another Arteriole.
The Nephron
 The nephron is the functional unit of the kidney. They process blood to form
urine. There are approximately 1 million nephrons per kidney.
 Anatomy of the nephron
o The glomerulus and Bowman’s (glomerular) capsule is collectively called
the renal corpuscle. The Bowman’s capsule surrounds the glomerulus,
with the first layer of Bowman’s capsule being simple squamous
epithelium, which allows substances to cross the epithelium.
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The capillaries are porous, which allows solute-rich fluid to pass
from the blood into the capsule.
 There are three layers of the glomerular capillary wall
 The fenestrated capillary endothelial layer keeps blood
cells from blocking the glomerular filter.
 The basement membrane or basal lamina is an intermediate
filter that keeps out only larger plasma proteins.
 The most selective filtration is at the diaphragms of the slit
pores, formed by the podocytes.
 Mesangial cells are located around the glomerular capillaries that
contract in response to hormones and paracrine agents to decrease
the surface area available for filtration.
 This can be considered a modified blood vessel, therefore any
disease affecting the blood vessels will affect the kidney.
o Proximal tubule
 This 3cm tubule comes off and drains the Bowman’s capsule. This
is an area of enormous amounts of metabolic movement. Simple
cuboidal epithelium with prominent brush border of dense
microvilli is located here to accomplish secretion and absorption.
Brush border increases the surface area, actively absorbing
substances from the filtrate.
 It is composed of both a convoluted section and straight portion
that leads into the Loop of Henle
 Sodium is actively transported out of the proximal tubule to the
peritubular blood in exchange for hydrogen ions. This creates an
electrical gradient so that chloride passively follows the sodium.
Water will also follow by osmosis. 65-85% of the salt and water in
the original glomerular filtrate is reabsorbed back into the blood
here along with 100% of amino acids, glucose, vitamins, and
ketones.
o Loop of Henle
 This portion of the nephron is composed of both descending and
ascending limbs. The ascending limb leads to the distal convoluted
tubule.
 The descending limp is simple squamous epithelium and is
permeable to water.
 The ascending limb is divided into a thin portion made of
simple squamous epithelium and a thick portion made of
simple cuboidal epithelium.
 The purpose of the loop is to recover the remainder of water and
concentrate urine. 15% of filtered water and 25% of filtered salt is
returned to the vascular system. As the loop descends, solutes of
the interstitial fluid of the medulla outside the tubule increase in
concentration, increasing the osmotic force for water flow out of
the tubule. Thus, in the descending limb, water and salt passively
leave the tubule. In the ascending limb, chloride and sodium are
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actively pumped out of the tubule. The ascending limb is
impermeable to water making the tubule fluid more dilute,
therefore it is called the diluting segment.
 It uses a countercurrent multiplier principle to produce increasing
concentration gradient. That is, the ascending and descending
limbs are in close proximity to each other and “enhance” the
concentration effects of each other.
 The vasa recta is a special U-shaped type of peritubular capillaries
surrounding the loop of Henle that originates from the efferent
arterioles of the juxtamedullary nephron. The capillary
arrangement of blood flow through the medulla is important for
maintaining the osmotic gradient set up by the loop of Henle.
o Distal tubule
 This comes up right in between the afferent and efferent arterioles.
It is also made of simple cuboidal epithelium. It lacks microvilli
and secretes solutes into the filtrate.
 This is relatively impermeable to water. It keeps the tubular fluid
dilute. This is the site of sodium reabsorption and is controlled by
aldosterone.
o Juxtaglomerular Apparatus
 This is composed of cells from the distal tubule, as well as cells of
the afferent and efferent arterioles. Cells of the distal tubule make
up the specialized area called the macula densa, which is a large
portion of the juxtaglomerulus apparatus along with the
juxtaglomerulus cells. This area secretes renin. The
juxtaglomerular apparatus functions in doing most of the
monitoring of the various functions of the kidney.
o Collecting duct
 This terminates at the renal papillae marking the end. It collects
urine from the multiple nephrons and runs through the medullary
pyramids, fusing to form the papillary ducts at the renal pelvis. It is
composed of simple cuboidal epithelium.
 This area is responsible for all of the “fine tuning” of the urine
production. It is impermeable to water, but not salt. Water is drawn
out by osmosis until the exiting urine is very concentrated. Urea us
passively reabsorbed here. Permeability of the collecting tubule to
water is controlled by ADH.
Types of nephrons
o Superficial nephron (85%)
 Its renal corpuscle is located a superficial area of the kidney’s
cortex. The vast majority of the entire nephron is in the cortex, yet
a part of the loop of Henle does dip into the medulla.
o Midcortical nephron
 Its renal corpuscle is located in the middle of the cortex. Part of its
loop of Henle dips into both the outer and inner medulla.
o Juxtamedullary nephron (15%)
 Its renal corpuscle is located next to the medulla, in the corticomedullary border. Here, the efferent arteriole gives rise to a special
type of capillary called the vasa recta.
o Note that all of the renal corpuscles are located in the cortex, and all of the
nephrons have loops of Henle that dip into the medulla. The closer the
renal corpuscle is to the medulla, the deeper the loops of Henle dip into
the medulla.
Renal Physiology
Glomerular Filtration (aka Ultrafiltration)
 This is the movement of fluid out of the glomerular capillaries and into the renal
tubule. All substances that are not attached to proteins are filtered.
 About 20% of the cardiac output (1L) goes to the kidney per minute, which means
that the entire blood supply goes through the kidney every 5 minutes. 10% of
blood flow (20% of plasma flow) is filtered per minute, forming 100-125mL of
filtrate per minute and 150-180L (45 gallons) per day.
o When fluid enters Bowman’s capsule, it is called filtrate. Fluid leaving the
renal papilla and entering the renal pelvis is called urine.
 The process of filtration requires that the blood move across the endothelium,
basement membrane of the endothelium, basement membrane of the epithelium of
the Bowman’s capsule, and through the epithelium of the capsule (through
podocytes) to enter the tube. The high hydrostatic pressure (blood pressure) is the
primary force driving glomerular filtration, forcing blood plasma from the
glomerulus into the surrounding Bowman’s capsule. The two forces opposing this
are the hydrostatic pressure inside Bowman’s capsule and the plasma oncotic
pressure (colloidal osmotic pressure), resulting from the protein concentration
difference across the membrane.
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o Net filtration pressure: Hydrostatic pressure (60mmHg) – Pressure inside
Bowman’s capsule (15mmHg) – Oncotic pressure (27mmHg) = 18mmHg.
 This is the pressure that initiates urine formation by forcing an
essentially protein-free filtrate of plasma out of the glomeruli and
into Bowman’s space and then down the tubule into the renal
pelvis. This small force causes a great amount of filtration.
o When it comes to blood flow, also remember that the glomerular
capillaries are different from other capillaries. They are larger in diameter,
fenestrated, and have a pressure of 60mmHg inside, which is much higher
than the regular systemic capillary pressure of 15-30mmHg due to the
larger diameters and less resistance.
Filtration includes both steric and charge barriers. The basement membrane,
which is negatively charged, serves as the primary barrier, opposing the
movement of negatively charged proteins. Generally the walls only allow for
passage of small molecules (molecular weight of less than 10,000). Molecules
larger than 65,000 do not get filtered. This includes large plasma proteins such as
serum, albumin, globulins, and fibrinogen. Consequently the filtrate in Bowman’s
corpuscle is protein-free plasma. Proteins that remain unfiltered attract water,
helping resist the hydrostatic pressure in the blood.
Glomerular filtration is rather nonselective, and both useful substances and waste
products are presented to the tubules. The final urine differs from the glomerular
filtrate in both volume and composition. Most of the valuable constituents of the
filtrate (most of the salts, water, and metabolites) are returned to the blood by the
tubules.
Glomerular filtration rate is generally stable and will vary only a little. This is due
to renal autoregulation. The juxtaglomerular apparatus stabilizes glomerular
filtration by regulating the afferent and efferent arteriole. It is controlled by the
effects of locally produced chemicals on the afferent arterioles. The macula densa
in the juxtaglomerular apparatus detects two components of filtrate in the tubule.
Regulation
o Kidneys will remain a rate of urine formation over a wide range of mean
arterial pressures (70-180mmHg). Due to autoregulation, when pressure
falls toward 70mmHg, the afferent arterioles dilate, and when the pressure
rises greater than 180mmHg, the vessels constrict.
o Renal blood flow
 An increase in the rate of blood flow through the nephrons greatly
increases the glomerular filtration rate.
o Afferent Arteriolar Constriction/ Obstruction
 Afferent arteriolar constriction/ obstruction decreases the rate of
blood flow into the glomerulus and also decreases the glomerular
pressure. Both of these effects decrease the filtration rate.
o Sympathetic Stimulation
 Decreased blood pressure causes increased sympathetic stimulation
of the kidneys. Here there is vasoconstriction of the afferent
arterioles, thereby decreasing the glomerular filtration rate,
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decreasing the urine production, increasing the blood volume, and
therefore increasing the blood pressure. .
Arterial pressure
 The glomerular filtration rate usually increases only a few percent
even when the mean arterial pressure rises from its normal value to
as high as 150mmHg.
Efferent arteriolar constriction
 This increases the resistance to outflow from the glomeruli. It
obviously increases the glomerular pressure, and small increases in
the efferent resistance often cause a slight increase in the
glomerular filtration rate. However, the blood flow decreases at the
same time, and if the degree of efferent arteriolar constriction is
moderate or severe, the plasma will remain in the glomerulus for a
long period of time, and extra large portions of plasma will filter
out. This will increase the plasma colloid osmotic pressure to
excessive levels, which will cause a paradoxical decrease in the
glomerular filtration rate despite the elevated glomerular pressure.
Volume
 If the macula densa senses an increase in the volume of filtrate, it
will release signaling molecules that cause vasoconstriction of the
afferent arteriole so that blood flow into the glomerulus is reduced,
returning the glomerular pressure and filtration rates back to
normal.
Electrolyte concentration
 As the fluids ascend the ascending loop of Henle, much of the
electrolyte concentration is removed. With excess filtrate, there is
not enough time for removal of electrolytes. This is why a high
concentration of electrolytes reflects a high glomerular filtration
rate. In response, the afferent arterioles will vasoconstrict. Low
electrolyte concentration is a sign of decreased filtration rate. In
response, the afferent arterioles will vasodilate, and the efferent
arterioles will vasoconstrict.
Tubular Reabsorption
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This is the movement of items such as glucose, ions, amino acids, and water out
of the renal tubule, with most of it entering the peritubular capillaries.
Reabsorption is the reason that the majority of the filtrate does not appear in the
urine. The result is a hypertonic urine.
There are two potential routes for reabsorption. First, it can go via diffusion
between the tubular cells across the tight junctions. The second route is
transcellular transport via active transport. The substance has to cross first the
luminal membrane (separating the lumen from the cell interior) and then the
basolateral membrane.
An example of reabsorption via diffusion is urea. It diffuses between the cells via
the concentration gradient. Most substances must use active transport due to the
polarity of the cells and substances.
To move water, sodium must be moved out of the filtrate. The sodium within the
filtrate is moved into the tubule via facilitated diffusion and pumped out of the
basolateral portion of the epithelial cell by primary active transport. The
basolateral membrane has sodium pumps to pump sodium out of the cell into the
interstitial tissue. This keeps the concentration of the sodium in the cell low, so
that sodium moves by facilitated diffusion on the other end. 65% of filtered
sodium is reabsorbed in the proximal tubule, so 65% of the water is reabsorbed.
Approximately 99% of filtrate is reabsorbed, while 1% is excreted. With diuretics,
96% is reabsorbed and 4% excreted.
Other substances are reabsorbed as well, such as potassium, chloride, and almost
100% of the amino acids, glucose, vitamins, ketone bodies, and molecules that are
useful to the body. These are all reabsorbed in the proximal tubule, and
sometimes the thick ascending loop of Henle.
o Potassium and chloride reabsorption is powered by the reabsorption of
sodium. Since they are moving in the same direction, this is an example of
cotransport.
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o Generally 100% of glucose that is filtered is reabsorbed. A stark exception
to this is patients with diabetes where the amount of glucose in the blood
exceeds the normal limit (80-100mg/dl) due to a hormonal mechanism
dysfunction. Due to the carrier mechanism and saturation kinetics, at a
concentration of about 315mg/ml glucose, the glucose cannot be
reabsorbed anymore and the glucose ends up in the urine. Every substance
that is filtered and reabsorbed has a transport maximum, depending on the
concentration that normally appears in the filtrate and how much is
reabsorbed. The transport maximum value is about 375 mg/min for
glucose. If there is more than 375 mg of glucose filtered per minute, then
glucose will appear in the urine.
 This does not mean that the average patient does not have glucose
in their urine. One just needs to exceed the sugar intake level in a
short period of time. The difference is that those with diabetes have
glucose in their urine almost all the time, because there is not
enough insulin to cause the glucose to enter the cells.
 Due to the fact that glucose is osmotically active as it goes through
the collecting duct and it carries water with it when it is being
excreted, polyuria and polydipsia occurs. Therefore, more water is
excreted and dehydration is more common.
Reabsorption sites
o The thick portion of the ascending loop of Henle is the site of sodium and
chloride reabsorption, as well as potassium and H+. The thin loop
reabsorbs water.
o The distal tubule is the site of sodium reabsorption.
o The collecting duct reabsorbs urea and water.
o The proximal tubule reabsorbs sodium, potassium, HCO3-, magnesium,
and chloride.
Tubular Secretion
 This is the movement of substances such as acids, bases, and ions from the
peritubular capillaries into the lumen. This occurs mainly of the distal tubule, but
sometimes in the proximal tubules. Secretion increases the rate of removal of
substances from the blood. Sometimes this is good (toxins), and sometimes it is
bad (medicine).
 Important secretions
o H+ and K- are moved from the tubular cells into the filtrate as sodium
moves into the cell via countertransport.
o Creatinine and choline
o Other toxins are secreted as well, i.e. penicillin.
 Secretion accounts for the maintenance of the blood pH, potassium concentration
in the blood, and nitrogenous waste concentration in the tubules.
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Renal Clearance
o This is the volume of plasma from which that substance is completely
cleared by the kidneys per unit time. Every substance has its own distinct
clearance value. This can be further broken down into the equation
CS = US * V / PS
where CS is the clearance of S, US is the urine concentration of S, V is the
urine volume per unit time, and PS is the plasma concentration of S.
o For clinical reasons, the creatine clearance, (CCr) is commonly used to
approximate the glomerular filtration rate, GFR. An increased
concentration of creatinine in the urine indicates decreased kidney
function. Due to the fact that there is no reabsorption and only a little
amount of secretion with this molecule, it can be used as a good
estimation, but it slightly overestimates the GFR. This can lead to the
generalization that any substance that raises the GFR can be assumed to
cause secretion. Less GFR would be due to reabsorption.
Summary
Part of the Nephron
Glomerulus
Function
1. Filtration
Proximal Tubules
1. Reabsorption by
active transport
2. Reabsorption by
diffusion
3. Reabsorption of
water by osmosis
(65% salt and water)
Loop of Henle: Descending
1. Reabsorption by
passive diffusion
1. Reabsorption by
active transport into
interstitial fluid or
renal medulla. A
counter current
multiplier is used.
1. Reabsorption by
active transport
2. Facultative water
reabsorption by
osmosis (ADH
controlled)
3. Secretion by
diffusion
4. Secretion by active
transport
Loop of Henle: Ascending
Distal and convoluted
collecting tubules
Substance Removed
1. Water, ions, amino
acids, glucose
1. Sodium, ions,
nutrients, glucose,
amino acids,
vitamins, ketones
(100%)
2. Chloride,
bicarbonate, 50%
urea
1. NaCl (25%) and
Water (15%)
1. NaCl (not followed
by water
reabsorption) since
it is impermeable to
water.
1. Sodium, and some
ions
2. Water
3. Ammonia
4. Potassium,
Hydrogen, and some
drugs
Water Regulation
 One characteristic of the kidneys is the fact there is an ability to excrete a
hypertonic urine. If an istonic (300 mOsm) urine was excreted, the volume would
be enormous. So to secrete this hypertonic urine, water is conserved.
o Diabetes Insipidus is due to the lack of the hormone ADH. With DI, there
is near isotonic urine. The most extreme form of this requires urinating
40L per day, which is equivalent to two Sparkletts water bottles. The
patient would also have to ingest this much. Treatment with engineered
hormones is available to help with this.
 When the body needs more water to maintain homeostasis, more water is retained
by the kidneys. When excess water is present, more water is excreted.
 Mechanism to conserve water
o In the nephron, the descending loop of Henle is located next to the
ascending loop of Henle, allowing circulation of electrolytes through the
interstitial tissue.
 The filtrate in the proximal tube will have the same osmotic
pressure as the blood.
 The osmolarity goes from 300 to 1200 mOsm as the filtrate
descends the descending limb. Water moves from the lumen of the
tubule into the interstitial tissue, concentrating the electrolytes in
the filtrate. Because the tissue has high levels of sodium and
chloride, they enter the tubule, also increasing the osmolarity of the
filtrate. This continues until the turnaround point. This osmolarity
of the filtrate equals that of the interstitial tissue, about 1200
mOsm.
 The ascending loop of Henle is impermeable to water. As it goes
up, sodium and chloride comes out. Going up, the electrolytes
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transport out of the thick ascending loop of Henle. Sodium is
moved out of the limb with chloride via secondary active transport.
o In the collecting duct, urea moves to the descending loop of Henle along
with sodium and chloride. This drives the osmolarity to 1200 mOsm. 50%
of this is due to urea and 50% due to sodium chloride.
o ADH controls the permeability of the collecting duct.
Function of the Vasa recta
o This originates in the cortex, so the blood coming into it will have an
isotonic osmolarity, but it supplies the medulla. It dips deep into the
medulla, where the osmolarity of the interstitial tissue will increase from
isotonic to extremely hypertonic. This is due to the fact that the capillaries
are freely permeable to water and electrolytes. Therefore, solute from the
hypertonic interstitium enters the descending limb of the vasa recta and
water comes out, increasing the osmolarity. As the blood makes the turn
and starts to ascend, water moves into the capillary and solute moves out,
because the osmolarity of the blood is greater than the interstitium. Solute
is being recycled during this process. By the time the blood leaves the
medulla, it is slightly hypertonic.
o The hypertonicity of the medullary interstitium is preserved because
 Blood flow occurs via the vasa recta (allowing osmotically active
particles to be recycled)
 The medullary interstitium receives less blood flow than other
body tissues.
o If there was just a blood vessel going through and leaving the medulla
without this countercurrent type of arrangement, all of the electrolytes
would simply be washed away, and the tonicity would remain isotonic.
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Vasopressin (ADH)
o This is a nonapeptide hormone that controls the permeability of the distal
tubule and collecting duct. It is synthesized in the hypothalamus and
transported to the posterior pituitary by axonal transport. The tonicity of
blood is monitored by osmoreceptors in the hypothalamus. If the
osmoreceptors detect an increase in osmolarity of the blood, they will
cause action potentials in the neurons that synthesize ADH and release it
into the capillaries of the posterior pituitary, and then travel to the kidney.
 It is a hormone and not a neurotransmitter, because it is actually
traveling in the blood, affecting structures further away than
neurotransmitters.
o ADH is released in response to increased solute concentration in plasma
and causes increased reabsorption of water, less excretion of water, and a
more concentrated urine. Decreased levels of ADH cause the opposite.
o This works, because ADH stimulates the production of cAMP which
increases the number of water channels in the cell membrane of the
collecting duct cells. These channels are increased in two ways. It either
moves existing water channels into the membrane or makes new water
channels. Vesicles are formed by the process of endocytosis. The vesicle
migrates to the membrane and fuses with it. These channels are
automatically inserted into the membrane.
o If there is excess water (low osmolarity), ADH secretion is inhibited.
Water reabsorption is minimal producing a dilute urine. Caffeine and
alcohol (diuretics) both inhibit ADH secretion, and thus more dilute urine.
A higher concentration of ADH would lead to maximal water
reabsorption, and therefore a more concentrated urine. Normally, 99% of
the water is reabsorbed.
pH Regulation
 In general, urine tends to be acidic (pH =6). It can go as low as 4 with extreme
amounts of H+. Carriers of the secreted hydrogen include phosphate (NaHPO4-),
ammonia (NH3  NH4+) from ammonium picking up an extra ion, or as sulfate.
 Kidneys regulate blood pH by excreting hydrogen ions in the urine and by the
retention and production of bicarbonate. When the blood is acidic, hydrogen is
excreted and bicarbonate (a base) is reabsorbed into the blood. The opposite
occurs when the blood is basic.
 Reabsorption of HCO3.
o The bicarbonate ion (HCO3-) is one of the most important buffers in the
blood. The handling of HCO3- and H+ is a much more important process
than the handling of hydroxyl groups (OH-), which tend to not be much of
a problem.
 Metabolic acidosis is a much more common issue than alkalosis,
because increased pH (alkalosis) can easily be reduced by holding
one’s breath for a short period of time.
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o Filtration leads to reabsorption, which occurs in the proximal cells.
Bicarbonate cannot cross the tubule proximal wall so it is converted to
carbonic acid which can cross the wall. The process is as follows:
 A Combination of a secreted H+ + HCO3- ion 
Carbonic acid (H2CO3)
 The carbonic acid then dissociates into H2O and CO2, which enters
the tubular cells where they are converted back into carbonic acid
by the enzyme carbonic anhydrase.
 The carbonic acid then redissociates into HCO3- and H+.
 HCO3- moves across the basolateral membrane by the process of
facilitated diffusion.
 Note that the HCO3- that enters is different than the one that leaves.
If there is an increase in H+ in the blood, the process of
reabsorption of HCO3- takes place, because it is needed in the
blood as a buffer. It does so by binding H+ forming H2O and CO2,
where the CO2 can be exhaled, removing the H+.
Formation of additional HCO3-.
o H20 and CO2 combine within the tubular cell forming carbonic anhydrase.
The carbonic anhydrase dissociates into H+, which is pumped by primary
active transport into the tubular lumen. HCO3- is moved into the interstitial
fluid by countertransport with Cl-. This process accomplishes pH
regulation by forming new HCO3- and secreting H+.
Sodium and Potassium Regulation
 In normal individuals, sodium excretion is increased when there is a sodium
excess in the body, and the opposite occurs when there is a deficit. Most of these
reflexes are initiated by various cardiovascular baroreceptors, such as the carotid
sinus.
 Sodium and potassium balance is regulated in the distal tubule by aldosterone.
 Aldosterone
o This is a steroid hormone (mineralocorticoid) secreted by the adrenal
cortex. The secretion is controlled by the juxtaglomerular apparatus,
which measures the filtrate osmolarity and volume.
o Aldosterone promotes sodium retention and potassium loss from the blood
by stimulating reabsorption of sodium and secretion of potassium across
the wall of the distal tubules. This controls the extracellular fluid volume,
therefore controlling the blood pressure regulation.

A decrease in arterial pressure is detected by the
juxtaglomerular apparatus, resulting in the secretion of the
proteolytic enzyme, renin which cleaves proteins into
smaller fragments. Renin is used to convert
Angiotensinogen from the liver into Angiotensin I, which is
later cleaved further to become Angiotensin II by
angiotensin converting enzymes, primarily from the lungs.
Angiotensinogen is always found circulating in the blood.
Angiotensin II stimulates the production of aldosterone
from the adrenal cortex, causing vasoconstriction to
increase arterial pressure.
o Renin is the rate-limiting factor. Its control includes
the renal sympathetic nerves, the intrarenal
baroreceptors, and the macula densa.
 Angiotensinogen II Pharmacological Effects
o Elevation of blood pressure
o Contraction of smooth muscle
o Mediates release of aldosterone
o Release of catecholamines from adrenal medualla
and adrenergic nerves
o Depresses reuptake of catecholamines by adrenergic
nerves
o Aldosterone primarily affects cells in the distal tubule and the cortical
collecting duct to increase reabsorption of sodium. It induces the synthesis
of proteins in its target cells, in this case proteins involved in sodium
transport.


65% of sodium is reabsorbed in the proximal tubule, and another
5% can be reabsorbed in the distal tubule and the cortical
collecting duct due to stimulation by aldosterone.
If an increase in the reabsorption of sodium is required, the amount of
sodium in the tubule cells is decreased by pumping more out into the
interstitium. Aldosterone increases primary active transport of sodium out
of the distal tubule and cortical collecting duct cells. This is done by
 Increasing the affinity of the sodium pump mechanism for ATP
 Increasing the amount of ATP available
 Increasing the number of pump sites
By decreasing the sodium in the cell, it increases the concentration
gradient across the luminal membrane.
o With regards to the sodium/potassium pump, pumping potassium into the
cell would cause it to diffuse out of the cell into the lumen of the tubule.
At the same time sodium is being reabsorbed, potassium is secreted. This
is the primary mechanism for decreasing potassium in the blood. The
effect of increased potassium stimulates aldosterone secretion. This has a
direct effect on the adrenal cortex.
o Aldosterone controls both sodium and potassium. This is a problem in
patients that take a lot of diuretics or drink large amounts of water,
because it leads to aldosterone secretion above normal levels, causing
decreased potassium in the blood (hypokalemia, which can cause heart
attacks).
Hormones working in opposition to Aldosterone
o Atrial Natriuretic Hormone
 This is a polypeptide hormone that is made in the atria of the heart.
 It is released in response to increased filling of the atria (excess
sodium), promoting natriuresis (sodium excretion) by decreasing
sodium reabsorption in the thick ascending limb of the loop of
Henle.
 This hormone also causes vasodilation of the afferent arteriole and
vasoconstriction of the efferent, increasing the glomerular capillary
pressure, which increases glomerular filtration, therefore
increasing the amount of sodium filtered and excreted.
o Urodilantin
 This is synthesized in the juxtaglomerular apparatus in response to
increased sodium. Urodilantin has the same function as ANH.
Calcium Regulation
 Both high and low levels of extracellular calcium can have varying, and even
serious problems with health. The three effector sites of calcium include the
bones, kidneys, and gastrointestinal tract. About 99% of total body calcium is
concentrated in the bone. 60% of plasma calcium is filterable at the renal
corpuscle, with most of it being reabsorbed. The rest is bound to plasma protein.
 Parathyroid Hormone
o This is produced by the parathyroid glands embedded in the surface of the
thyroid gland. Decreased plasma calcium concentration stimulates
parathyroid hormone secretion, with an increased amount doing the
opposite.
o This hormone has four effects.
 It increases the resorption of bone, which results in the movement
of calcium from bone into extracellular fluid.
 It stimulates the activation of vitamin D
 It increases renal tubular calcium reabsorption, thus decreasing
urinary calcium excretion.
 It reduces the tubular reabsorption of phosphate, this raising the
urinary excretion and lowering the extracellular concentration.
 1,25-dihydroxyvitamin D3, aka 1,25-(OH)2D3
o This is the active form of Vitamin D. it is metabolized by addition of
hydroxyl groups, first in liver cells, and then in kidney cells. Since it is
made in the body, it is considered a hormone and not a vitamin.
o The main action of 1,25-(OH)2D3 is to stimulate the intestine to actively
absorb the calcium ingested in food.
Micturition

This is the process of urine removal from the bladder.

The bladder is located retroperitoneally on the floor of the pelvis. In males, it lies
immediately in front of the rectum. The prostrate gland surrounds the neck of the
urethra. In females, it lies anterior to the vagina and uterus. Its body is a thinwalled, smooth, collapsible, muscular sac with a transitional epithelium, meaning
that it goes from many layers of squamous epithelium to only a few layers as the
bladders distends. It is in the shape of a three-sided pyramid with its apex pointed
anteriorly. The interior of the bladder has openings for the ureters from the kidney
and the urethra, which drains the bladder.
The detrusor muscle is located in the middle layer of the three walls of the
bladder. It consists of circular smooth muscle while both the inner and outer
layers are longitudinal.




There are two sphincters to the bladder- the trigone (internal sphincter) and the
external sphincter. When the bladder is relaxed, the trigone collapses the opening
into the urethra, closing it. The external sphincter is a circular structure of skeletal
muscle surrounding the neck of the bladder. Its contraction prevents urination.
The bladder normally holds about 500ml of urine, with a maximum of about
1,000ml, if necessary.
By stretching the muscles, depolarization occurs and urine is strewn along the
path from the kidney to the bladder. As the bladder fills (about 300-400ml), there
are stretch receptors in the walls of the bladder which cause a parasympathetic
reflex to occur. Action potentials go to the sacral region of spinal cord,
stimulating efferent parasympathetic fibers to go back to the bladder and cause
contraction. When the ditrusor contracts, pressure in the bladder increases 4060mmHg, opening the internal sphincter. The opening of the internal sphincter
causes fluid to press on the external sphincter giving the sensation of having to
urinate. Urination can be voluntarily prevented via descending pathways that
stimulate the motor nerves to the external sphincter and simultaneously inhibit the
parasympathetic nerves to the detrusor muscle. By voluntarily allowing the
external sphincter to relax, urine will flow.
Renal Pathology
Introduction
 This is an extremely complex structure, with complex functions and vasculature.
Because of this reason, the kidney is the target organ of a host of systemic
diseases such as immune problems, diabetes, hypertension, etc.
 It takes about 90% loss of kidney function before signs and symptoms of
pathology begin to develop. Therefore, smoldering diseases leading to loss of
kidney tissue manifest very late. The average person only needs 10% to function.
This is why a patient can donate a kidney and suffer no consequences. Remaining
nephrons take up the slack of those lost. The amount of filtration in each nephron
increases significantly, meaning that the remaining glomeruli become
hyperpermeable.
Infections
 Low blood flow (profusion) to the medulla causes difficulty fighting off
infections, which can eventually lead to kidney failure. Kidney infections
generally arise from bladder infections since the bladder is connected to the
kidney by the ureter. These infections can be prevented by drinking a lot of fluids
and by urinating when necessary, as well as taking antibiotics should an infection
arise.
Renal Failure
 Nearly any kidney disease can lead to 90% loss, leading to kidney failure.
o Azotemia is the retention of nitrogenous metabolic waste products.
o Uremia is the biochemical and clinical changes due to renal failure.
 It is due to the accumulation of nitrogenous waste products,
extreme edema, acidosis, excess potassium, etc. Death due to renal
failure is generally due to acidosis. Increased H+ content tends to
suppress action potentials and synaptic activity. High potassium
concentration can cause death as well.
 Kidney function is measured with BUN and creatine in a chemistry panel.
o Increased BUN and creatine indicate renal failure, yet this does not show
up until 90% damage.
 Clinical manifestations/ problems associated with failure of the system include:
o Body fluids will become out of balance with failure. This usually leads to
edema from salt and water retention. Edema is first seen in the eyelids,
then the ankles.
o Body electrolyte (K, Na, Cl, Ca, etc.) balance is out of balance with
kidney failure. High potassium values seen clinically can cause heart
fibrillations.
o Normally, the pH is 7.35-7.45. Kidney failure leads to acidosis due to the
loss of HCO3- and metabolic acid production. This causes disruption in the
cellular environment, decreased enzymes, etc. resulting in possibly death.
o Metabolic waste products are retained with failure, leading to azotemia
and uremia.


o Kidney failure leads to bone marrow suppression from “poisons” and
decreased erythropoietin. This decreases red blood cells, leading to
anemia.
o There is a marked elevation in blood pressure with kidney failure, due to
salt and water retention and increased renin.
Acute Renal Failure
o This occurs when the kidneys abruptly stop working entirely. The onset is
very rapid (10-14 days), and full recovery is possible.
o Causes
 An abrupt dramatic decrease in blood pressure, either because the
heart stops beating or there is a huge loss of blood. This can lead to
a decrease in blood flow to the kidney, causing it to be very
susceptible to anoxia (loss of oxygen).
 A heart attack can evoke the CNS Ischemic Reflex, where
blood flow to the kidney is blocked by the body so that
blood may get to the brain. This is why patients that have
had heart attacks could have massive kidney damage.
 Poisons- heavy metals (Hg, Pb)
 Infusion reactions where the wrong blood type is infused.
 Acute glomerulonephritis
 Other causes include renal obstructions, embolism, either extra or
intrarenal, bladder rupture, vascular diseases, interstitial nephritis,
pigment induction, and complications related to pregnancy.
o Consequences
 Due to the rapid deterioration of renal function, there is an
accumulation of nitrogenous waste in the blood that would
normally be excreted in the urine.
 Edema from excess water, electrolytes, and nitrogenous waste
products and other organic molecules.
 Can be lethal if a significant enough number of nephrons are
affected. Patient should be put on immediate dialysis.
Chronic Renal Failure
o This is the loss of function, usually due to progressive loss in the number
of nephrons. Multiple effects on many differentiated tissues are seen.
o Causes
 Diabetes is the most common cause and can affect the kidneys by
drastically increasing the rate of atherosclerotic plaque formation
in the renal arteries. It also causes a thickening of the basement
membrane due to an accumulation of the glycosylated end
products which reduces the movement of substances across the
capillary, reducing filtration.
 Chronic glomerulonephritis
 Other causes include hypertension, lupus, infections like
tuberculosis and pyelonephritis, polycystic kidney disease, and
obstructions.
Glomerular Disease
 Nephrotic Syndrome
o This is a noninflammatory disease of the glomerular apparatus. It is due to
a host of primary kidney diseases and is often associated with systemic
diseases like diabetes, autoimmune diseases, etc. It is common.
o The initial event is glomerular basement membrane derangement with
increased permeability to protein (primarily albumen). The increased
protein decreases the serum level and the osmotic pressure leading to fluid
transfer to the tissues and more salt and fluid retention via
renin/angiotensin/aldosterone to maintain the intravascular volume. The
decreased albumin decreases lipid transport and metabolism, therefore
increasing the amount of lipids.
o Signs
 Generalized edema, seen around the eyelids first.
 Decreased colloidal osmotic pressure means the ability to
retain fluid in the blood is dramatically decreased, causing
excessive edema.
 Massive proteinuria- bubbly urine!
 Hypoalbuminemia- decreased protein causing increased swelling
due to a decreased oncotic pressure.
 Hyperlipidemia and hyperlipiduria
 Nephritic Syndrome
o This is an acute inflammatory renal disease characterized by
 Hematuria- blood in the urine, due to inflammation
 Oliguria and the resultant retention of waste products (decreased
urine output)
 Moderate Proteinuria
 Hypertension
 Mild edema usually of the eyelids and face first, which is much
less than seen in the nephrotic syndrome.
 Azotemia
o This is polygenic, mainly due to the glomerulus becoming
hyperpermeable. A host of inflammatory diseases can cause the nephritic
syndrome. The diseases classified with glomerulonephritis are usually
immune mediated diseases, such as cross reactivity in streptococcal skin
infections and lupus.
o The inflammation damages the glomerular capillary wall, resulting in the
red blood cells and proteins to cross the glomerular capillary to escape into
the renal tubular lumen and urine, giving rise to hematuria and proteinuria.
This also decreases the filtration capabilities, leading to oliguria.
o Types
 Acute
 This often develops 1 to 2 weeks after a group A betahemolytic streptococcus infection of the throat, or less
commonly the skin. The body forms antibodies against the
proteins in the bacterium. The antigen-antibody complexes


get wedged in the basement membrane between the tubule
and the glomerulus, causing an inflammatory response. The
proliferation of cells of Bowman’s capsule can thicken the
capsule to the point where filtration cannot occur. Biopsy
shows proliferation of endothelial mesangial and epithelial
cells and exudation of neutrophils and monocytes. Serum
complement levels are low and antistreptococcal
exoenzyme titers are elevated.
 Most patients retain or regain normal renal function but are
at risk for hypertension. Clinically over 95% of children
recover. Most of the remainder develop a rapidly
progressive form of the disease, and a few progress to
chronic renal failure. In adults, the epidemic form has a
good prognosis, but only 60% recover after the sporadic
form. The remainder develop rapidly progressive disease,
chronic renal failure, or delayed, but eventual resolution.
Chronic
 This is an immunologic disorder. The mechanism is similar
to acute glomerulonephritis, except that the precipitating
organism is not Streptococcus. It stems from a variety of
other organisms that can cause chronic conditions, not
resolvable in a few weeks. The infection is not actually in
the kidney, but the inflammatory response is set-up by an
antigen-antibody complex. The patient remains
asymptomatic for years with an insidious loss of renal
function over years. The patient presents with diffuse
sclerosis of glomeruli, proteinuria, hematuria, and usually
hypertension.
Rapid Progress
 An unknown absence of an immune complex is the
hallmark. Pathological features include focal and
segmented necrosis and epithelial cell proliferation in most
glomeruli. Clinical features include fulminant renal failure,
proteinuria, hematuria, and red blood cell casts.
Pyelonephritis
 This is inflammation in the interstitium of the kidney and the tubules and not
primarily in the glomeruli. Usually the renal pelvis is involved too, hence the term
“pyelo.” There are a number of etiologies but the most common is bacterial
infection, namely E.Coli.
o Acute Pyelonephritis is almost always caused by the bacteria getting to the
kidney retrograde via the bladder and ureters. It is suppurative and usually
very responsive to antibiotics. Clinically there is fever, dysuria, flank/back
pain, and pyuria. This is almost exclusively seen in females due to a
shortened length and location of urethra, and is especially common during
pregnancy.
o Chronic Pyelonephritis is often a slow progressing and insidious disease
which slowly destroys the kidneys. It is usually due to an ongoing,
unresolved, bacterial infection. Often the only signs and symptoms are
“fatigue, don’t feel well” and other vague symptoms. There is usually a
little puss in the urine. There is often an undiagnosed history of “kidney
infections” which leads to serious complications that warrant renal
dialysis. The patient needs to be treated and followed until it is completely
gone. It shows up in urine tests with white blood cells.
Cystitis (Bladder Infection)
 This is very common, and is seen more in women. Inflammation interferes with
ureter function and urine goes back up with bacteria. If it gets back to the kidney,
it is then pyelonephritis.
Urinary Outflow Obstruction
 This is a blockage of the flow of urine usually occurring in the ureters.
 Urolithiasis (Kidney Stone)
o The formation of a calculus (stone) the size of a pin head in the collecting
system. This tends to be polygenic and occurs when the patient becomes
dehydrated or has other metabolic problems. Calcium, magnesium, and
uric acid are most common causes.
o When the stone is moving in the ureter, it tends to be very painful. Pain
starts first in the flank and groin (scrotum and labia majora), then in the
ureter is where it is in a band, low near the bladder in the anterior low
abdomen, with sensations in the tip of the urethra. This leads to hematuria
as sharp edges tear the ureter. This also leads to the smooth muscle spasm
and intense waves of pain.
o Treat with ultrasound to crush the stones.
Tumors
 The primary concern is malignant tumors. The kidneys are glandular/epithelial
tissue, therefore tumors here are carcinomas.
o It is more common in males and more common in young/midlife, i.e.
Wilm’s Tumor
 Renal Cell Carcinoma accounts for 90% and is 2/1 male dominated. It usually
leads to hematuria and flank pain with other systemic signs of a cancer-like
weight loss, fatigue, etc.
 Transitional Cell Carcinoma originates on the mucosal surface of the collecting
system. Carcinogens are commonly cleared in the urine and in high concentration
in the kidney and collecting system.
o This leads to bladder cancer. This is (highly malignant) due to the
transitional epithelium histology of the bladder.
Treatments
Dialysis
 Dialysis is simply the act of separating substances using a membrane.
 Hemodialysis
o A shunt is placed in both an artery and vein. Blood will then leave the
body and go through a dialyzer, consisting of a cellophane membrane that
allows molecules smaller than a protein to escape. The tubing rests inside
of a fluid that contains ions in concentrations similar to that of plasma. As
blood goes through, an equilibrium is set up between the fluid surrounding
the membrane and the blood within it.
o Patients with acute renal failure may undergo this process for only days or
weeks. Someone with total renal failure undergoes this process 3-4 times a
week for 6-8 hours each session. A trained technician must be there the
entire time, and it is a very expensive process. People on dialysis live
about five years and usually die from infections.
 Peritonial
o The patient connects themselves to a machine that pumps fluid into their
abdomen where it stays there for two hours and is then pumped out. This
is less expensive and can be done in home. The rate of serious infection is
greatly reduced, yet it is a lot less effective.
 The treatment of choice for those with chronic renal failure is a kidney transplant.
Diuretics
 These are more commonly known as water pills. They increase renal water
excretion of solute and water. Most do this by decreasing renal tubular
reabsorption of sodium chloride and water.
 The regulation of extracellular fluid volume is a very important medical maneuver
for controlling blood pressure among other systemic problems. It is the first line
of treatment. Diuretics are also used to treat edema, congestive heart failure,
pregnancy, premenstrual tension, and to control the renal toxicity of certain other
drugs. Their efficacy may be predicted from their site of action.
 They work depending on the ability to increase solute excretion through one of
the following mechanisms
o Increasing the glomerular filtration rate.
o Decreasing the rate at which sodium is reabsorbed from the glomerular
filtrate by the renal tubules.
o Promoting the excretion of sodium by the kidney.
 Osmotic diuretics
o Mechanism- Inhibition of reabsorption of water
 These are molecules that are administered and are not reabsorbed
due to their large size. As they pass through the tubule, they will
increase the osmolarity of the filtrate in the collecting duct,
creating less of a difference between the filtrate and the interstitial
tissue. This causes less of a tendency for water to move out of the
filtrate at the proximal tubule, descending limb, and collecting
tubule, increasing the volume of urine.
o Agents
 Mannitol (Osmitrol)
 This is the most common agent and is administered
intravenously.
 Mannitol is not metabolized, decreasing the extracellular
fluid volume. The osmotic pressure of the blood is
increased and then freely filtered, but not reabsorbed,
increasing the osmolarity of the filtrate.
 This is not prescribed for chronic treatment, because it has
to be infused directly into a vein. It is used in emergency
situations, and the blood pressure needs to be lowered fairly
quickly, i.e., acute diuresis for intracranial surgery. It has a
short duration of action (2-3 hours) and safe, with very
little side effects.
 Glycerol
 This is administered orally, and is very sweet. Since it is a
carbohydrate, it should not be given to those with diabetes.
 Urea is administered intravenously.
 This is not as effective as mannitol mole for mole because
it is reabsorbed to some extent (50%) by the renal tubules.
 Isosorbide (Isordil) is administered orally.
o Uses





Edema
Glycerol and isosorbide can reduce IOP.
Mannitol is used in the treatment of intracranial pressure and
hypertension.
o Adverse effects
 Initial hypertension
 Headache, nausea, vomiting, and expansion of extracellular fluid
 Mannitol can cause hyponatremia or hypernatremia (unpredictable)
Carbonic Anhydrase Inhibitors
o Mechanism- Inhibition of carbonic acid formation
 Inhibiting carbonic anhydrase reduces the reabsorption of
bicarbonate in the proximal tubule. Bicarbonate is osmotically
active, so it increases the osmolarity of the filtrate. These have
only a mild diuretic effect since the loop of henle is able to
reabsorb the excess NaCl.
o Agents
 Acetazolamide (Diamox)
 This was the first tolerated oral diuretic.
 Methazolamide (Neptazane)
 Dichlorophenamide (Daranide)
 This is used mainly for respiratory acidosis.
o Uses
 Prevent/treat altitude sickness
 Treat POAG
 Alkalinize the urine (increases HCO3- in urine, making the diuretic
work longer)
 Elevated systemic bicarbonate
o Adverse effects
 Metabolic acidosis (increased HCO3- in urine)
 Renal stones
 CNS depression
 Hypokalemia
Thiazide diuretics (Thiazides)
o These are long-acting agents whose hypotensive effects are due to
decreased blood volume and arterial dilution.
o Mechanism- Inhibition of chloride reabsorption in the thick ascending
portion of the Loop of Henle and in the early distal tubule, resulting in 510% excretion of NaCl.
o Agents
 Chlorothiazide (Diuril)
 This is a p-carboxy cogener of sulfanilamide.
 Hydrochlorothiazide (Hydrodiuril, Esidrix)
 Chlorthalidone (Hygroton)
o Uses
 Treat edema




Treat HTN and CHF
Treat DI
 Increases water put out through the kidneys
 Prevents urine dilution and decreased urine output by 50%
(paradoxical)
o Adverse effects
 Weakness, paresthesia, carbohydrate intolerance.
 Increased plasma uric acid (gout)
 Potassium depletion (hypokalemia)
 Metabolic alkalosis- neutralize with CA Inhibitor
Loop Diuretics
o These are very powerful, short-acting diuretics. They are derived from two
types of chemistry, sulfonamides and sulfhydryl-reactive.
o Mechanism- Inhibition of sodium and chloride reabsorption in the thick
ascending portion of the loop of henle. These reduce or abolish the
osmotic gradient of the medulla by inhibiting chloride and sodium
reabosrption.
 30-40% of the sodium chloride is normally reabsorbed in the
ascending loop, and there are no sites downstream capable of
reabsorbing so large a load. Because of the strong potency, these
can be life-saving drugs. Although these are effective, there is a
“high ceiling effect.”
 The problem encountered with this medication is that keeping the
sodium in the filtrate tends to result in potassium excretion,
because retained sodium causes aldosterone secretion, increasing
sodium reabsorption in the distal tubule, leading to excess
secretion of potassium. So, potassium supplements must be taken.
 Loop diuretics decrease medullary hypertonicity, which increases
the volume of the urine.
o Agents
 Furosemide (Lasix)- lasts 6 hours
 Ethacrynic acid (Edecrin)
 Bumetanide (Bumex)
o Uses
 Treat edema, especially in patients with low glomerular filtration
rates.
 Treat hypertension
 Treat pulmonary edema
o Adverse effects
 Increased plasma uric acid
 Dehydration
 Potassium depletion (hypokalemia)
 Metabolic alkalosis
Sodium Channel Blockers
o These are also known as Potassium Sparing Diuretics or Aldosterone
Antagonists, because they do not have the effect of increasing potassium
secretion. The problem with these is that they are not that powerful since
only 5% of urinary NaCl is normally reabsorbed at this site, so they are
given with small amounts of loop diuretics.
o Mechanism- Blockade of aldosterone receptors and sodium channels in
the collecting ducts.
o Types
 Spironolactone (Aldactone)
 This is the only aldosterone antagonist. It takes time to
develop its effect.
 Mechanism- promotes increased sodium and chloride
excretion and reduced potassium excretion.
 Uses
o Treat hyperaldosteronism
o Counteract potassium loss induced by other
diuretics
o Treat edema
 Triamterene (Dyrenium) and Amiloride (Midamore)
 Probable mechanism- Inhibition of renal epithelial sodium
channels
 Use: counteract potassium loss induced by other diuretics
o Adverse effect- hyperkalemia, CI irritation, and leg cramps
Summary
Class
CAI
Loop Diuretics
Thiazides
K-sparing diuretics
Mechanism
Inhibit secretion of H+; this
causes less reabsorption of
sodium and bicarbonate
Inhibit Na, K, 2Cl
cotransport in luminal
membrane
Inhibit Na, Cl cotransport in
luminal membrane
Inhibit action of
aldosterone. Also block Na
channels in luminal
membrane.
Major Site Affected
Proximal Tubules
Ascending loops of Henle
Distal convoluted tubule
Cortical collecting ducts
Uricosuric Agents



Gout is associated with increased body stored of uric acid. Acute attacks involve
joint inflammation caused by precipitation of uric acid crystals. These agents are
used to increase the urinary excretion of uric acid and decreases serum urate
levels.
Mechanism
o It competes with uric acid in the renal tubule for reabsorption by the weak
acid carrier mechanism. At low doses, they may also compete with uric
acid for secretion by the tubule and can elevate the serum uric acid
concentrations.
o They act primarily on the kidneys, but inhibit the secretion of other weak
acids in addition to inhibiting the reabsorption of uric acid.
Types
o Benemid (Probenecid)
 Used for the treatment of hyperuricemia associated with gout and
gout arthritis.
o Anturane
 Its pharmacological activity is the potentiation of the urinary
excretion of uric acid. It is useful in reducing the blood urate levels
in patients with chronic gout and acute intermittent gout, and for
promoting the reabsorption of tophi.
 Contraindication for patients with peptic ulcers and gastrointestinal
inflammation.
o Sulfinpyrazone
o Other drugs used in gout include colchicine (inhibits inflammation of
acute gouty arthritis), indomethacin, allopurinol, and aspirin.