09-Jun-15

KIDNEYS
 Kidneys are the functional units of the urinary
system

 Excretion of the body waste material is usually

thought to be a sole function performed by the
kidneys

URINARY SYSTEM  Kidneys perform a number of functions, apart from

this excretory function, which are described below
Muhammad Haseeb

Functions of the Kidneys EXCRETORY FUNCTIONS

i. Excretory Functions  Kidneys eliminate;
ii. Regulation of Electrolyte & Water balances  Waste products of metabolism, that are no longer
iii. Regulation of body fluid osmolality and needed by the body such as urea, creatinine, uric acid,
electrolyte concentrations hemoglobin and hormonal metabolites
iv. Regulation of acid base balance
v. Regulation of arterial pressure  Toxic chemicals and other foreign substances produced
endogenously or taken from outside such as drugs,
vi. Secretion, metabolism, and excretion of
pesticides and additives
hormones
vii. Gluconeogenesis

Water and Electrolyte Balance FLUID INTAKE AND OUTPUT

 Kidneys play a pivotal role in regulation of water  Body fluids are kept balanced by continously
and electrolyte balance in the body exchanging them with the;
 For maintenance of homeostasis excretion of water
and electrolytes must match the intake  External environment

THINK ???  Within the different compartments of the body

 What will be the consequences if there is an
imbalance in the intake and excretion?

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Daily Intake of Water Daily Loss of Water

 Water is added to the body by two major sources
 1- Ingestion of liquids and food: Usually 2100 1-Insensible Water Loss:
ml/day is added to body fluid
 2- Synthesized in the body as a result of oxidation  This is the unconscious loss of water. For example
of carbohydrates : adding about 200 ml/day continuous loss of water by evaporation from the
 So, total intake of water is 2300 ml/day respiratory tract and diffusion through the skin, that
 Intake of water ,however, is variable in different together accounts for 700 ml/day
people and within a single person

Daily Loss of Water Daily Loss of Water

2- Fluid Loss in Sweat: 3-Water Loss in Feces:
 Amount of water loss in sweating is highly  Only a small amount 100 ml/day is lost in feces.
variable, depending upon physical activity and  This can increase to several liters a day in people
environmental temperature with severe diarrhea
 The volume of sweat is about 100 ml/day, but in a 4- Water loss by the Kidneys:
very hot day or during extraneous exercise it may  The remaining water loss is through the kidneys
be increased up to 1-2 L/day
 The rate of urine excretion by the kidneys is
 Thirst mechanism comes into play
controlled by multiple mechanisms

Regulation of Arterial Pressure Acid Base Balance

 Kidneys play a dominant role in long-term  Acid base balance is regulated by excreting acids or
regulation of arterial pressure by Balancing the regulating the body fluid buffer stores
water and sodium
 Protein metabolism products such as sulfuric acid
 While short term arterial pressure is regulated by and phosphoric acid are eliminated only by the
secretion of renin that lead to formation of kidneys
vasoactive products e.g. angiotensin II

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Erythrocyte Production Production of Calcitriol

 Kidneys secrete erythropoietin, which stimulates  Kidneys produce the active form of vitamin D,
the production of red blood cells. Almost all the 1,25-dihydroxyvitamin D3 (calcitriol)
erythropoietin secreted in the circulation is through
kidneys  Calctriol is essential for regulation of calcium and
phosphate, especially in deposition of calcium in
 Reno-compromised patients develop severe anemia bones and reabsorption through GIT
as a result of decreased erythropoietin production

Gluconeogenesis Kidney disease / Renal Failure

 Kidneys synthesize glucose from amino acids and  These homeostatic functions are disrupted and
other precursors during prolonged fasting, a severe abnormalities of body fluid volumes and
process referred to as gluconeogenesis composition occur
 With complete renal failure enough potassium,
 Kidney rivals the liver in adding glucose to the acids, fluid and other substances accumulate in the
blood, in periods of prolonged fasting body to cause death within a few days
 In these settings clinical interventions such as
hemodialysis are initiated

 There are two body fluid compartments

BODY FLUID  INTRACELLULAR FLUID COMPARTMENT

COMPARTMENTS  EXTRACELLUALR FLUID COMPARTMENT

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Intracellular Fluid Compartment Extracellular Fluid Compartment

 About 28 – 42 liters of fluid in the body are inside  All the fluids outside the cells are collectively
the 100 trillion cells and collectively called called the Extracellular Fluid
intracellular fluid
 It contains almost 12 liters or 20 % of the total
body weight
 So, it constitutes 40% of the total body weight

 There are two compartments of the ECF

 Fluid of each cell contains its individual mixtures 1- Interstitial Fluid -11 liters
of different constituents, but concentrations of these
2- Plasma- 3 liters Non-cellular part of blood
substances are similar from one cell to another

Blood Volume FUNCTIONAL ANATOMY

 Blood contains both the extracellular fluid (fluid in
the plasma) and intracellular fluid (Fluid in the
RBCs)
 Blood is considered to be a separate compartment
because it is contained in its own compartment, the
circulatory system
 Average blood volume is 7% or about 5 Liters
 60% plasma and 40 % PCV

FUNCTIONAL ANATOMY Kidney- Functional Anatomy

 The two kidneys lie on the posterior wall of the
abdomen
 In an adult human, approx weight of each kidney is
150 grams and is about the size of clenched fist
 The medial side of each kidney contains an
indented region called hilum through which pass
the renal artery, vein, lymphatics, nerve supply and
ureter
 Surrounded by tough, fibrous capsule

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 Upon bisection, two distinct regions of the kidney  The outer border of the pelvis is divided into open
could be visualized; ended pouches called major calyces, that extend
 Outer Cortex downward and divide into minor calyces
 Inner Medulla  These calyces collect urine from the tubules of each
 The medulla is divided into 8 – 10 cone shaped papilla
masses of tissues called renal pyramids  The walls of the calyces, pelvis, and ureter contain
 Base of each pyramid originates at the border contractile elements that propel the urine toward
between medulla and cortex and terminates in the the bladder, where urine is stored until it is emptied
papilla by micturition

FUNCTIONAL ANATOMY FUNCTIONAL ANATOMY

RENAL BLOOD FLOW RENAL BLOOD FLOW

 Blood flow to the kidney is normally about 22% of
the cardiac output, or 1100 ml/min
 Renal artery enters the kidney through hilum and is
branches progressively to form three arteries;
1- Interlobar arteries
2- Arcuate arteries
3- Interlobular areteries / radial arteries
4- Afferent Arterioles

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RENAL BLOOD FLOW Renal Capillary Circulation

 Afferent arterioles lead to glomerular capillaries,  The renal circulation is unique in having two
where urine is formed by filtration of solutes & capillary beds, separated by efferent arterioles
fluid (except the plasma proteins) 1- Glomerular Capillaries
2- Peritubular Capillaries
 The distal ends of the glomerular capillaries
coalesce to form the Efferent Arterioles, that lead to  Kidneys regulate the hydrostatic pressure by
peritubular capillary network that surrounds the adjusting resistance of the efferent and afferent
renal tubules arterioles, thereby changing the rate of renal
processes

RENAL BLOOD FLOW

 High hydrostatic pressure in glomerular capillaries
(60 mmHg) causes fluid filtration
 While lower hydrostatic pressure in peritubular
capillaries (about 13 mmHg) causes rapid
reabsorption
 Peritubular capillaries empty into vessels of the
venous system, and progressively form interlobular
vein, arcuate vein, interlobar vein, and renal vein

NEPHRON NEPHRON
 The functional unit of the kidney is nephron
 Each kidney in humans contains 1 million
nephrons, each capable of forming urine
 Kidney can not regenerate new nephrons*
 Each nephron has two parts
1-Glomerulus – A tuft of glomerular capillaries
2- Renal tubule – Consists of different parts and
filtered fluid is converted into urine here

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GLOMERULUS RENAL TUBULES

 It contains a network of network of capillaries 1- Proximal Convoluted Tubule:
called glomerular capillaries. This is the first coiled section of the renal tubular
 These capillaries are covered by epithelial cells, system
and the total glomerulus is encased in Bowman’s This portion lies in the cortex and receives the
Capsule glomerular filtrate from the Bowman’s Capsule.
 Fluid filtered from the glomerulus flows into
bowman’s capsule. Epithelium is attenuated, 400 A’ Size: 15 mm long and 55 micrometer in diameter
 Capillary endothelium is fenestrated with an Epithelium: columnar and contains microvilli
incomplete basement membrane, allowing
filtration*

2- Loop of Henle: Distal Convoluted Tubule

 It is a U-shaped structure, and dips into the renal  Beyond the macula densa, fluid enters into the
medulla distal convoluted tubule, which is last coiled
 Each loop consists of descending and an ascending portion of nephron
limbs  This is present in the cortex
 The walls of the descending limb and lower portion
of ascending limb are very thin* and immediate  Size: 5mm long
after this Loop has a much thicker walls called  Epithelium: cells are smaller and have no brush
Thick ascending limb of Loop of Henle** borders
 At the end of thick part a small portion called
macula densa is present

Collecting Tubules and Ducts Types of Nephron

 DCT is followed by connecting tubule and cortical 1- Cortical Nephron:
collecting tubule, which lead to the cortical Nephrons that have glomeruli located in the outer
collecting ducts, that coalesce to form single larger cortex are called Cortical Nephrons. They have
collecting duct that runs into the medulla, and short Loop of Henle that penetrate short into
becomes medullary collecting ducts medulla –70 – 80 %
 The collecting ducts merge to form progressively 2- Juxtamedullary Nephron:
larger ducts that eventually empty into the renal 20 – 30% of nephrons have glomeruli lie deep in
pelvis at the tips of pyramids the cortex near medulla and Loop of Henle dip
deeply into medulla

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Regional Differences in Nephron

 The vascular structures supplying the

juxtamedullary nephrons also differ from those
supplying the cortical nephrons

 For the cortical nephrons entire tubular system is

surrounded by an extensive network of peritubular
capillaries

Functions of Nephron
 For the juxtamedullary nephrons long efferent Glomerular Filtration:
arterioles extend from the glomeruli down into the
outer medulla and then divide into specialized
peritubular capillaries called Vasa recta In the kidneys, a fluid that resembles plasma is
 This vasa recta extends downward into the medulla filtered through the glomerular capillaries into renal
and lie side by side with Loop of Henle, where it tubules, and the filtered fluid is called glomerular
goes to cortex, along with Loop of Henle filtrate
 In the cortex it empties into the cortical veins
 This specialized cap network play in formation of
conc. urine

Tubular Reabsorption: Urine Formation:

As this glomerular filtrate passes down the tubules,  Solutes are secreted into tubular fluid to form the
water and ions are reabsorbed in the tubules. A urine which enters in the renal pelvis
process called Tubular reabsorption
Tubular Secretion:
Solutes that do not get reabsorbed, are secreted  The processes, involved in the urine formation, are
through renal tubular process called tubular conducted in such a manner that they conserve
secretion, and the resultant fluid is called tubular important electrolytes and metabolites while wastes
fluid are eliminated in the urine

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Urinary Bladder
 Homeostasis (ECF) is maintained by adjusting the  Two main parts;
urine composition 1- Body – Major part and collects urine
2-Neck – Funnel like extension of the body
 From the renal pelvis, the urine passes to the connected to urethra
bladder and is expelled to the exterior by the  Smooth Muscle of the bladder is called detrusor
process of urination, or micturition muscle
 Bladder neck is 2 – 3 cm long made up of detrusor
muscle and elastic fibers muscle in this region is
called internal sphincter, cause urination on
pressure threshold

Male & Female Bladder

Juxtaglomerular Apparatus
 This is the combination of structures that lie near to 2- The Lacis Cells:
the glomerulus that are; These cells are granular and are in closed contact
with macula densa
1-Macula Densa: 3- The Juxtaglomerular cells:
It is a group of modified epithelial cells in the These are also granular and present after the
portion of the DCT lying in contact with afferent glomerulus in afferent arterioles
glomerulus of the same nephron Granulation in the JGCs cause the secretion of
renin,which is determined by sodium concentration
of the macula densa

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Composition of Urine
Definition:
This is a pale yellow colored fluid of slightly acidic
in nature, excreted by the kidneys
Volume:
In a normal adult the volume of excreted urine is
1000 – 2000 mL
Color:
Pale yellow or amber depends upon the pigment
called Urochrome

Composition of Urine Composition of Urine

pH:
Mean: 6 (Normal Range 4.5 – 8.0) Odor:
Chemical Nature: Aromatic but becomes ammonia like upon standing
Acidic Turbidity (cloudiness):
Specific Gravity:
Fresh urine is usually transparent
Normal: 1.002 - 1.028
But it may be increased in diabetes melitus due to Turbid urine does not necessarily indicate a
the presence of glucose and decreased in diabetes pathological condition
insipidus

Normal Constituents Abnormal Constituents

A) Organic Substances: 1- Proteins:
Urea, Uric Acid, Creatinine, Creatine, Ammonia, Albumin, Globulins or Bence Jhons Proteins
Oxalic Acid, Allantoin, Vitamins 2-Sugars:
Glucose, fructose, galactose, lactose and Pentose
B) Inorganic Substances: 3-Blood:
Sodium, Chloride, Phosphate, Sulphate, Potassium, RBCs, WBCs
Calcium, Magnesium, Iodine 4-Ketone Bodies:
5-Others:
Casts, Pus, Renal calculi, Microbes

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Factors regulating the Urine Volume Factors regulating the Urine Volume
1-Blood Pressure: 3- Diuretics:
The cells of the juxtaglomerular apparatus are
particularly sensitive to change in the BP These are the drugs or chemicals that induce a
When renal BP falls below normal, it is being raised by state of an increased urine. Coffee, alcohol, tea
renin – angiotensin system 4-Permeability of Glomerulus:
2-Volume Concentration:
The volume of urine is directly related to
The concentration of water and solutes in blood also
affect the urine volume permeability of glomerular membrane. Anything
Osmotic receptors in the hypothalamus play an that reduces the permeability will cause decreased
instrumental role in ADH secretion* urine output
5-Emotions: due to increased BP

Urine Formation Normal GFR

Glomerular Filtration:
It is the process by which large amount of fluid is  The glomerular filtration rate in a healthy person is
filtered through glomerular capillaries into approximately 125mL/min which means 7.5L/h, or
Bowman’s Capsule 180 L/d
 This filtered fluid is called glomerular filtrate, and  The values are 10% lower than those in men
the process is termed as glomerular filtration  Whereas, the normal urine output is 1 L/d
 Glomerular filtration is the first step in urine  Thus 99% or more of the filtrate is normally
formation reabsorbed

THINK……..?????? Composition Of G. Filtrate

 One might question, filtering such large amount of  It is a plasma like fluid in composition, having the
water and solutes then reabsorbing almost 99% of same conc. Of salts and organic molecules
these substances?  The glomerular filtrate is essentially protein free,
 One advantage of high GFR is that it allows the because like most capillaries, glomerular capillaries
are also impermeable to proteins.
kidneys to remove waste products from the body.
Most wastes are poorly reabsorbed from tubules  It is also devoid of cellular elements, including
RBCs
therefore depend upon GFR
 Low molecule substances i.e. Ca++ and fatty acids
 GFR allows the kidneys to control the volume and are not freely filtered because they are partially
composition of the body fluids* bound to plasma proteins*

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Glomerular Capillary Membrane Capillary Membrane

 The glomerular capillary membrane has one
distinct feature in comparison to other capillaries,
that they have 3 layers (instead of usual two)
1- Capillary endothelium
2- basement membrane
3- Podocytes (layer of epithelial cells), that
surround outer surface of basement membrane

Capillary Endothelium Basement Membrane

 The capillary endothelium is perforated by
thousands of small holes called fenestrae  Basement membrane consists of a meshwork of
 These are similar to fenestrated capillaries found in collagen and proteoglycan, that have large spaces
liver but the fenestrations are;
1-Relatively large  Water and small solutes are can freely filter through
these spaces
2-Negatively charged in a fixed manner
 Pores are 70 -90 nm in diameter  Proteoglycans have strong negative electrical
charges on their surface

Podocytes Capillary Membrane

 This is the final part of the glomerular capillary
membrane, consisting of epithelial cells that line
the outer surface of the glomerulus
 These cells are not continuous rather they have
footlike processes or projections (psuedopodia)
called podocytes
 These projections form filtration slits, each 25nm
wide, and are also negatively charged

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Permeability of Capillary Memb. 1-Diameter & Permeability

 The permeability of the glomerular capillaries is  Neutral substances with effective molecular
about 50 times greater that of capillaries in skeletal diameter of less than 4 nm are freely filtered
muscles
 Permeability of glomerular capillaries depend upon
following factors  While neutral substances with diameter more than
1- Substance Size / Diameter 8nm approaches zero
2- Substance Charge
3- Size of the Capillary bed  Between these values filtration is inversely
4- Hydrostatic and Osmotic Pressure proportionate to diameter / molecular weight of the
substance

Relative GF of Different Solutes 2-Electrical Charge & Permeability

 The negatively charged molecules less likely

filtered than positively charged molecules
 The molecular diameter of the plasma protein is
albumin is only about 6-7nm, whereas the pores of
the glomerular membrane are thought to be about
8nm (80 angstrom)
 But the albumin is negatively charged and filtration
of albumin is restricted in the membrane due to
negative electrostatic charges repulsion membrane
and albumin

Size of the Capillary Bed

 In kidney disease, such as nephritis, the negative  If the area of the capillary bed is reduced largely, it
charges in the glomerular membrane are dissipated will also reduce the GFR
even before there are noticeable changes in kidney  Contraction and dilation of capillary lumen
histology, a condition called minimal change determine the blood flow
nephropathy  There are certain factors that determine the blood
 As a result of this loss, could be freely filtered and flow
appear in the urine a condition known as  Angiotensin II is an important factor that mediate
proteinuria or albuminuria blood flow to the glomerular capillaries

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Hydrostatic & Colloid Pressure 1) Net Filtration Pressure:

Determinant of the GFR: This term refers to the sum of the hydrostatic and
The GFR is determined by colloid osmotic forces that either favor or oppose
1) Net Filtration Pressure:
filtration across the glomerular capillaries
The sum of the hydrostatic and colloid osmotic forces
across the glomerular membrane, gives the net These forces include;
filtration pressure 1) Hydrostatic pressure inside the glomerular
(2) Filtration Coefficient: capillaries (glomerular hydrostatic pressure, PG),
The glomerular capillary filtration coefficient is Kf
Equation Expressed mathematically which promotes filtration
GFR = Kf Net filtration pressure

Forces Causing GF
2) The hydrostatic pressure in Bowman’s capsule
(PB) outside the capillaries, which opposes filtration
3) The colloid osmotic pressure of the glomerular
capillary plasma proteins (ПG), which opposes
filtration
4) The colloid osmotic pressure of the proteins in
Bowman’s capsule (ПB)

1-Increased Kf Increases GFR

 Kf is glomerular capillary filtration coefficient  Because total GFR for both kidneys is about 125
 The Kf is a measure of the product of the ml/min and the net filtration pressure is 10 mm Hg,
the normal Kf is calculated to be about 12.5
conductivity and surface area of the glomerular ml/min/mm Hg of filtration pressure. When Kf is
capillaries. expressed per 100 grams of kidney weight, it
 The Kf cannot be measured directly, but it is averages about 4.2 ml/min/mm Hg, a value about
400 times as high as the Kf of most other capillary
estimated experimentally by dividing the rate of systems of the body;
glomerular filtration by net filtration pressure:  The average Kf of many other tissues in the body
Kf = GFR/Net filtration pressure is only about 0.01 ml/min/mm Hg per 100 grams.

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2- Bowman’ Capsule Hydrostatic

Pressure
 Increasing the hydrostatic pressure in Bowman’s  In certain pathological states associated with
capsule reduces GFR, whereas decreasing this obstruction of the urinary tract, Bowman’s capsule
pressure raises GFR. pressure can increase markedly, causing serious
 However, changes in Bowman’s capsule pressure reduction of GFR
normally do not serve as a primary means for  For example, precipitation of calcium or of uric
regulating GFR. acid may lead to ―stones‖ that lodge in the urinary
 Experiments demonstrate that its value in humans tract, often in the ureter, thereby obstructing
is 18 mm Hg outflow of the urinary tract and raising Bowman’s
capsule pressure

3- GC Colloid Pressure
 As blood passes from the afferent arteriole through  Normal colloid osmotic pressure of plasma entering
the glomerular capillaries to the efferent arterioles, the glomerular capillaries is 28 mm Hg, this value
the plasma protein concentration increases about 20 usually rises to about 36 mm Hg by the time the
per cent blood reaches the efferent end of the capillaries
 The reason for this is that about one fifth of the  Therefore, the average colloid osmotic pressure of
fluid in the capillaries filters into Bowman’s the glomerular capillary plasma proteins is midway
capsule, thereby concentrating the glomerular between 28 and 36 mm Hg, or about 32 mm Hg
plasma proteins that are not filtered

Glomerular Capillary Pressure

 Thus, two factors that influence the glomerular  Increased Glomerular Capillary Hydrostatic
capillary colloid osmotic pressure are 1) the Pressure Increases GFR
arterial plasma colloid osmotic pressure and 2) the  The glomerular capillary hydrostatic pressure has
fraction of plasma filtered by the glomerular been estimated to be about 60 mm Hg under
capillaries (filtration fraction). normal conditions. Changes in glomerular
hydrostatic pressure serve as the primary means for
 Increasing the arterial plasma colloid osmotic physiologic regulation of GFR
pressure raises the glomerular capillary colloid  Increases in glomerular hydrostatic pressure raise
osmotic pressure, which in turn decreases GFR GFR, whereas decreases in glomerular hydrostatic
pressure reduce GFR

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 Glomerular hydrostatic pressure is determined by 2) Afferent Arteriolar resistance

three variables, each of which is under physiologic Increased resistance of afferent arterioles reduces
control:
1) Arterial Pressure glomerular hydrostatic pressure and decreases GFR
Increased arterial pressure tends to raise glomerular Conversely, dilation of the afferent arterioles
hydrostatic pressure and, therefore, to increase increases both glomerular hydrostatic pressure and
GFR GFR

Mathematical Expression
3) Efferent Arteriolar Resistance; The GFR can therefore be expressed as;
 Constriction of the efferent arterioles increases the
GFR = Kf (PG – PB – ПG + ПB)
resistance to outflow from the glomerular Forces Favoring Filtration (mm Hg)
Glomerular hydrostatic pressure = 60
capillaries.
Bowman’s capsule colloid osmotic pressure = 0
 This raises the glomerular hydrostatic pressure, and
Forces Opposing Filtration (mm Hg)
as long as the increase in efferent resistance does
Bowman’s capsule hydrostatic pressure = 18
not reduce renal blood flow too much, GFR
Glomerular capillary colloid osmotic pressure = 32
increases slightly
Net filtration pressure = 60 – 18 – 32 = +10 mm Hg

Estimation of individual Substance

Autoregulation of GFR
Glomerular Filtration
 The rate at which each of these substances is  GFR is kept relatively constant at 125 ml/min,
filtered is calculated as despite wide variation in arterial pressure, this
Substance Filtration = called autoregulation of GFR
Glomerular filtration rate × Free Plasma  GFR and renal blood flow are autoregulated by
concentration feedback mechanisms that are intrinsic to the
 This calculation assumes that the substance is kidney. These mechanisms still function in blood
freely filtered and not bound to plasma proteins. perfused kidneys that have been removed,
For example, if plasma glucose concentration is 1 independent of systemic influences
g/L, the amount of glucose filtered each day is
about 180 L/day × 1 g/L, or 180 g/day

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Why GFR is autoregulated

 The GFR normally remains autoregulated (remains  In the absence of autoregulation, an increase in
relatively constant), despite considerable arterial blood pressure from 100 to 125 mm Hg would
pressure fluctuations cause a similar 25% increase in GFR i.e 225 L/day)
 For instance, a decrease in arterial pressure to as  If tubular reabsorption remained constant at 178.5
L/day, this would increase the urine flow to 46.5
low as 75 mm Hg or an increase to as high as 160 L/day—a total increase in urine of more than 30-
mm Hg changes GFR only a few percentage points fold
 Normally, GFR is about 180 L/day and tubular  Because the total plasma volume is only about 3
reabsorption is 178.5 L/day, leaving 1.5 L/day of liters, such a change would quickly deplete the
fluid to be excreted in the urine blood volume

Mechanism of GFR Autoregulation

 GFR is autoregulated by tubuloglomerular  The macula densa cells sense changes in volume
feedback (TGF), that links changes in sodium delivery to the distal tubule by way of signals
chloride concentration at the macula densa  Decreased GFR slows the flow rate in the loop of
 TGF consists of two mechanisms at the same time Henle, causing increased reabsorption of sodium
and chloride ions in the ascending loop of Henle,
for the GFR autoregulation thereby reducing the concentration of sodium
1) An afferent arteriolar feedback mechanism chloride at the macula densa cells
2) An efferent arteriolar feedback mechanism  This decrease in sodium chloride concentration
initiates a signal from the macula densa that has
two effects

1) It decreases resistance to blood flow in the  Renin released from these cells then functions as an
afferent arterioles, which raises glomerular enzyme to increase the formation of angiotensin I,
hydrostatic pressure and helps return GFR toward which is converted to angiotensin II
normal  Finally, the angiotensin II constricts the efferent
2) It increases renin release from the arterioles, thereby increasing glomerular
juxtaglomerular cells of the afferent and efferent hydrostatic pressure and returning GFR toward
arterioles, which are the major storage sites for normal
renin

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GFR Autoregulation Myogenic Mechanism

 Another mechanism that contributes to the
maintenance of a relatively constant renal blood
flow and GFR is the ability of individual blood
vessels to resist stretching during increased arterial
pressure, a phenomenon referred to as the myogenic
mechanism
 Small arterioles throughout the body have shown
that they respond to increased wall tension or wall
stretch by contraction of the vascular smooth
muscle

Dietary Factors
 Stretch of the vascular wall allows increased  Certain circumstantial factors may also increase the
movement of calcium ions from the extracellular GFR
fluid into the cells, causing them to contract  For example, a high protein intake is known to
through the mechanisms increase both renal blood flow and GFR
 This contraction prevents overdistention of the  With a chronic high-protein diet, such as one that
vessel and at the same time, by raising vascular contains large amounts of meat, the increases in
GFR and renal blood flow are due partly to growth
resistance, helps prevent excessive increases in of the kidneys. However, GFR and renal blood
renal blood flow and GFR when arterial pressure flow increase 20 to 30 %within 1 or 2 hours after a
increases person eats a high-protein meal

Regional Blood Flow & O2

Consumption
 The main function of the renal cortex is filtration of  On the other hand, maintenance of the osmotic
large volumes of blood through the glomeruli, so it gradient in the medulla requires a relatively low
is not surprising that the renal cortical blood flow is blood flow
relatively great and little oxygen is extracted from  It is not surprising, therefore, that the blood flow is
the blood about 2.5 mL/g/min in the outer medulla and 0.6
mL/g/min in the inner medulla
 Cortical blood flow is about 5 mL/g of kidney
 The PO2 of the medulla is about 15 mm Hg
tissue/min (compared with 0.5 mL/g/min in the (comparatively high) because metabolic work is
brain) being done, particularly to reabsorb Na+ in the
 The PO2 Of the cortex is about 50 mm Hg. thick ascending limb of Henle

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Tubular Reabsorption & Secretion

 This makes the medulla vulnerable to hypoxia if  As the glomerular filtrate enters the renal tubules, it
flow is reduced further flows sequentially through the successive parts of
 Nitric oxide, prostaglandins, and many the tubule—the proximal tubule, the loop of Henle,
cardiovascular peptides in this region function to the distal tubule, the collecting tubule, and, finally,
maintain the balance between low blood flow and the collecting duct—before it is excreted as urine
metabolic needs  Along this course, some substances are selectively
reabsorbed from the tubules back into the blood,
whereas others are secreted from the blood into the
tubular lumen.

General Considerations

 The tubular cells may add more of the substance to  The clearance of the substance equals the GFR if
the filtrate (tubular secretion), may remove some or there is no net tubular secretion or reabsorption,
all of the substance from the filtrate (tubular exceeds the GFR if there is net tubular secretion,
reabsorption), or may do both. Theses two and is less than the GFR if there is net tubular
processes will determine the amount of the reabsorption
substance excreted per unit of time

F-R-E- Rates of Different Sub.

Amount Amount Amount % filtered load
Substance
Filtered Reabsorbed Excreted Reabsorbed

Glucose 180 180 0 100

Bicarbonate
4,320 4,318 2 >99.9
(mEq/day)
Sodium
25,560 25,410 150 99.4
(mEq/day)
Chloride
19,440 19,260 180 99.1
(mEq/day)
Potassium
756 664 92 87.8
(mEq/day)
Urea
46.8 23.4 23.4 50
(g/day)
Creatinine
1.8 0 1.8 0
(g/day)

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From Table, two things are immediately apparent.  By controlling the rate at which they reabsorb
1- The processes of glomerular filtration and different substances, the kidneys regulate the
tubular reabsorption are quantitatively very large excretion of solutes independently of one another, a
relative to urinary excretion for many substances capability that is essential for precise control of the
2- Unlike glomerular filtration, which is relatively composition of body fluids
nonselective (that is, essentially all solutes in the
plasma are filtered except the plasma proteins or
substances bound to them), tubular reabsorption is
highly selective.

Mechanisms of Tubular
Tubular Reabsorption
Reabsorption and Secretion
 For a substance to be reabsorbed, it must first be
transported;

1) across the tubular epithelial membranes into the

renal interstitial fluid and then
2) through the peritubular capillary membrane back
into the blood

 water and solutes can be transported either through  Tubular reabsorption involves both active and
the cell membranes themselves (transcellular passive transport:
route) or through the junctional spaces between the  ACTIVE TRANSPORT:

cells (paracellular route) It can move a solute against an electrochemical

 Then, after absorption across the tubular epithelial gradient and requires energy derived from
cells into the interstitial fluid, water and solutes are metabolism
transported the rest of the way through the Primary Active Transport – Na / K ATPase
peritubular capillary walls into the blood by Secondary Active Trans. – Glucose Reabsorption
ultrafiltration

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 Water is always reabsorbed by osmosis

 Pinocytosis is the mechanism used to reabsorb
proteins, which attaches to the brush border of the
luminal membrane, and this portion of the
membrane then invaginates to the interior of the
cell until it is completely pinched off, and a vesicle
is formed containing the protein. Once inside the
cell protein is digested into amino acids, that are
reabsorbed through basolateral membrane into
interstitium. Pinocytosis is an active transport mech

Transport Maximum
 Substances that are actively reabsorbed or secreted,  The glucose transport system in PCT is a good
there is a limit to the rate of at which the solute can example
be transported, referred to as transport maximum  In adult human transport max for glucose is about
 The limit is due to saturation of specific transport 375 mg/min, whereas filtered load of glucose is
system involved when the amount of solute only about 125 mg/min
delivered to the tubule (tubular load) exceeds the  With large increases in the plasma glucose levels
capacity of the carrier proteins and specific filtered load reaches above 375 mg/min
enzymes involved in the transport  The excess glucose filtered is not reabsorbed and
excreted into urine

Paracellualr Pathway Proximal Convoluted Tubule

 Urea , chloride and certain other molecules are
passively reabsorbed through paracellular pathway
 Creatinine is a large molecule and is essentially
impermeant to tubular membrane, therefore none of
the creatinine is reabsorbed and passes along the
nephron into the urine

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PCT Membrane Solute Transport

 The PCT Membrane: Membrane surface of epithelial brush border has a lot of
1- PCT epithelial cells are highly metabolic and have protein carrier molecules, that transport large amount
of sodium across luminal membrane linked by way of
large number of mitochondria to support potent
co-transport mechanism with amino acids and glucose
active transport processes e.g. ATPase
The remainder of the sodium is transported from the
2- Cells have extensive brush border on the luminal tubular lumen into the cell by counter-transport
(apical) side of the membrane increasing SA* mechanisms, which reabsorb sodium while secreting
3- Extensive labyrinth of intercellular and basal other substances into the tubular lumen, especially
channels, also increase SA, for rapid transport of hydrogen ions
substances

 The secretion of hydrogen ions into the tubular

lumen is an important step in the removal of
bicarbonate ions from the tubule (by combining H+
with the HCO3 to form H2CO3, which then
dissociates into H2O and CO2
66% sodium ions
85% Sodium bicarbonate
65% potassium
60% water and virtually all glucose & amino acids

 There are some differences in the mechanisms by

which sodium and chloride are transported through
the luminal side of the early and late portions of the
proximal tubular membrane
 In the first half of the proximal tubule, sodium is
reabsorbed by co-transport along with glucose,
amino acids, and other solute

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Concentrations of Solutes Along

the Proximal Tubule
 But in the second half of the proximal tubule, little  Proximal convoluted tubule is highly permeable to
glucose and amino acids remain to be reabsorbed water, so that water reabsorption is comparable
 Instead, sodium is now reabsorbed mainly with with that of sodium reabsorption in PCT
chloride ions. The second half of the proximal  Organic solutes, such as glucose, amino acids, and
tubule has a relatively high concentration of bicarbonate, are much more avidly reabsorbed than
chloride (around 140 mEq/L) compared with the water, so that their concentrations decrease
early half, so more chloride is reabsorbed in the markedly along the length of the proximal tubule
second half

Secretion of Organic Acids and

Solutes Cleared As Such from PCT
Bases by the Proximal Tubule
 The proximal tubule is also an important site for
 Other organic solutes that are less permeant and not secretion of organic acids and bases such as bile
actively reabsorbed, such as creatinine, salts,oxalate, urate, and catecholamines
 Their concentration is increased along the proximal
tubule  Another compound that is rapidly secreted by the
proximal tubule is para-aminohippuric acid (PAH).

Loop of Henle

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 Three Parts of Loop Of Henle  The descending part of the thin segment is highly
1- The thin descending segment permeable to water and moderately permeable to
most solutes, including urea and sodium
2- The thin ascending segment  About 20 percent of the filtered water is reabsorbed
3-the thick ascending segment in the loop of Henle, and almost all of this occurs in
 The thin descending and thin ascending segments the thin descending limb
have thin epithelial membranes with no brush  The ascending limb, including both the thin and the
borders, few mitochondria, and minimal levels of thick portions, is virtually impermeable to water, a
metabolic activity characteristic that is important for concentrating the
urine

Thick Limb
 The thick segment of the loop of Henle, which  Other ions, such as calcium, bicarbonate, and
begins about halfway up the ascending limb, has magnesium, are also reabsorbed in the thick
thick epithelial cells that have high metabolic ascending loop of Henle
activity  Solute reabsorption in the thick ascending limb is
 About 25 percent of the filtered loads of sodium, also mediated by the Na/K ATPase pump in the
chloride, and potassium are actively reabsorbed in epithelial cell basolateral membranes
the loop of Henle, mostly in the thick ascending
limb

 The low intracellular sodium concentration in turn  There is also significant paracellular reabsorption
provides a favorable gradient for movement of of cations, such as Mg++, Ca++, Na+, and K+, in
sodium from the tubular fluid into the cell the thick ascending limb owing to the slight
positive charge of the tubular lumen relative to the
interstitial fluid
 In the thick ascending loop, movement of sodium  The thick ascending limb also has a sodium
across the luminal membrane is mediated primarily hydrogen counter-transport mechanism in its
by a 1-sodium, 2-chloride, 1-potassium co- luminal cell membrane that mediates sodium
transporter reabsorption and hydrogen secretion in this
segment

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Distal Convoluted Tubules

Distal Convoluted Tubules

 The thick segment of the ascending limb of the
loop of Henle empties into the distal tubule
 The very first portion of the distal tubule forms
part of the juxtaglomerular complex that provides
feedback control of GFR and blood flow in this
same nephron
 The next part of the distal tubule is highly
convoluted

Late Distal Tubule and Cortical

Collecting Tubule
 Approximately 5 percent of the filtered load of  The second half of the distal tubule and the subsequent
sodium chloride is reabsorbed in the early distal cortical collecting tubule have similar functional
tubule characteristics. Anatomically, they are composed of
 The sodium-chloride co-transporter moves sodium two distinct cell types
chloride from the tubular lumen into the cell, and 1- The principal cells
the sodium-potassium ATPase pump transports Na 2- The intercalated cells
into the cell
 The principal cells reabsorb sodium and water from
 Chloride diffuses out of the cell into the renal
the lumen and secrete potassium ions into the lumen.
interstitial fluid through chloride channels in the
The intercalated cells reabsorb potassium ions and
basolateral membrane
secrete hydrogen ions into the tubular lumen

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NaCl Reabs. & K+ Secretion in

NaCl Reabsorption in EDCT
Late DCT

DCT
 Both the late distal tubule and the cortical
collecting tubule segments reabsorb sodium ions,
and the rate of reabsorption is controlled by
hormones, especially aldosterone. At the same
time, these segments secrete potassium ions from
the peritubular capillary blood into the tubular
lumen, a process that is also controlled by
aldosterone and by other factors such as the
concentration of potassium ions in the body fluids

 The intercalated cells of these nephron segments avidly  The permeability of the late distal tubule and
secrete hydrogen ions by an active hydrogen-ATPase cortical collecting duct to water is controlled by the
mechanism, Hydrogen ion secretion by the intercalated concentration of ADH, which is also called
cells is mediated by a hydrogen-ATPase transport vasopressin
mechanism. Hydrogen is generated in this cell by the
action of carbonic anhydrase on water and carbon  With high levels of ADH, these tubular segments
dioxide to form carbonic acid are permeable to water, but in the absence of ADH,
they are virtually impermeable to water. This
 It is capable of secreting hydrogen ions against a large
concentration gradient, as much as 1000 to 1 special characteristic provides an important
mechanism for controlling the degree of dilution or
 Thus, the intercalated cells play a key role in acid-base
concentration of the urine
regulation of the body fluids

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 09-Jun-15

Medullary Collecting Duct

 These two areas are impermeable to urea  Although the medullary collecting ducts reabsorb
 Because potassium is not recycled here so there is less than 10 per cent of the filtered water and
no lumen positive charge to drive out Ca++ and sodium, they are the final site for processing the
Mg++ by electrical charges urine and, therefore, play an extremely important
 Rather Ca++ is actively reabsorbed by the DCT role in determining the final urine output of water
epithelial cell via an apical ca++ channel and and solutes
basolateral Na+/ Ca++ exchanger, and this process
is mediated by the PTH

 The permeability of the medullary collecting duct

to water is controlled by the level of ADH.With
high levels of ADH, water is avidly reabsorbed into
the medullary interstitium, thereby reducing the
urine volume and concentrating most of the solutes
in the urine

 Medullary Collecting Duct is permeable to urea  The medullary collecting duct is capable of
secreting hydrogen ions against a large
 Therefore, some of the tubular urea is reabsorbed concentration gradient, as also occurs in the cortical
into the medullary interstitium, helping to raise the collecting tubule. Thus, the medullary collecting
osmolality in this region of the kidneys and duct also plays a key role in regulating acid-base
contributing to the kidneys’ overall ability to form a balance
concentrated urine

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General Terminologies
 Obligatory Urine Volume:  Tubular Load:
Minimum volume of water that is required by the Total amount of a substance that filters through
solutes of the urine for their excretion glomerular capillary membrane into tubules each
minute
 Obligatory Reabsorption Of Water: Formula:
The amount of water that is reabsorbed in the proximal TL = Plasma Clearance GFR
convoluted tubule i.e. 65% Examples:
 Facultative Reabsorption of Water: Na: 18 mEq/min
Reabsorption of water that takes place in the late distal Urea: 33 mg / min
tubule and cortical tubule under the influence of ADH Glucose: 125 mg/min

Formation of Dilute & concentrated

Urine
 Threshold Conc. In Plasma:  Functional Considerations:
Every substance that has a tubular transport When it is necessary to conserve body water,
maximum has also a threshold concentration in kidney excrete urine with a high solute
plasma below which none of it appears in urine and concentration
above which progressively larger quantities appear When it is necessary to rid the body of excess
in urine water, the kidneys excrete urine with a dilute solute
concentration
The principal regulator of urine composition is
ADH – Absence & Presence of ADH

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Components of Concentrating and

Mechanism of Dilute Urine
Diluting the System
 The formation of urine that is dilute (hypo-osmotic to
plasma) or urine that is concentrated (hyperosmotic to
plasma), achieved by the counter current system of the
nephron, this system consists of ;
1- Descending limb of Loop of Henle
2- Thin & thick segments of the ascending LoH
3- Meduallry Intersititium
4- Collecting Duct
5- Vasa recta

Mechanism of Excreting Dilute

Urine
 When there is a large excess of water in the body,  The mechanism for forming a dilute urine is to
the kidney can excrete as much as 20 L/day of continue reabsorbing solutes from the distal
dilute urine, with a concentration as low as 50 segments of the tubular system while failing to
mOsm/L reabsorb water
 Fluid leaving the ascending loop of Henle and early
 To excrete excess water, it is necessary to dilute the distal tubule is always dilute, regardless of the level
glomerular filtrate (having osmolality 300 mOsm/L) of ADH
as it passes along the tubule. This is achieved by  In the absence of ADH,the urine is further diluted
reabsorbing solutes to a greater extent than water in the late distal tubule and collecting ducts, and a
large volume of dilute urine is excreted

Concentrated Urine –
Counter Current Mechanism

 A countercurrent system is a system in which the  The concentrating mechanism depends upon the
inflow runs parallel to, counter to, and in close maintenance of a gradient of increasing osmolality
proximity to the outflow for some distance along the medullary pyramids

 The concentration of urine is done through counter  This gradient is produced by the operation of the
current mechanism that is conducted by the loop of loops of Henle as countercurrent multipliers and
Henle and vasa recta in the peritubular capillaries maintained by the operation of the vasa recta as
in the juxtamedullary nephrons countercurrent exchangers

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Mechanism
 The osmolarity of interstitial fluid in almost all
parts of the body is about 300 mOsm/L, which is  The operation of each loop of Henle as a
similar to the plasma osmolarity countercurrent multiplier depends on the high
 The osmolarity of the interstitial fluid in the permeability of the thin descending limb to water
medulla of the kidney is much higher, increasing (via aquaporin-1), the active transport of Na+ and
progressively to about 1200 to 1400 mOsm/L in the Cl– out of the thick ascending limb, and the inflow
pelvic tip of the medulla of tubular fluid from the proximal tubule, with
outflow into the distal tubule

Step 1 Step 2
 Assume first a condition in which osmolality is 300  Next, the active pump of the thick ascending limb
mOsm/kg of H2O throughout the descending and on the loop of Henle is turned on, reducing the
ascending limbs and the medullary interstitium the concentration inside the tubule and in addition that
same as that leaving the proximal tubule the pumps in the thick ascending limb can pump
100 mOsm/kg of Na+ and Cl– from the tubular
fluid to the interstitium, increasing interstitial
osmolality to 400 mOsm/kg of H2O
 Limit to the gradient, maintained in the lumen, is
200 mOsm/kg, because some ions diffuse back

Step 3
 Water then moves out of the thin descending limb,
and its contents equilibrate with the interstitium
(osmotic equilibrium) However, fluid containing
300 mOsm/kg of H2O is continuously entering this
limb from the proximal tubule
 The interstitial osmolarity is maintained at 400
mOsm/L because of continued transport of ions out
of the thick ascending loop of Henle

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Step 4
 Step 4 is additional flow of fluid into the loop of
Henle from the proximal tubule, which causes the
hyperosmotic fluid previously formed in the
descending limb to flow into the ascending limb

Step 5 Step 6
 Once this fluid is in the ascending limb, additional  Then, once again, the fluid in the descending limb
ions are pumped into the interstitium, with water reaches equilibrium with the hyperosmotic
remaining behind, until a 200-mOsm/L osmotic medullary interstitial fluid
gradient is established, with the interstitial fluid
osmolarity rising to 500 mOsm/L

Step 7 Step 1-7

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Conc. Urine: Role of ADH ADH

ADH Feedback Mechanism Vasa Recta : CC Exchanger

 Plasma flowing down the descending limb of the
vasa recta becomes more hyperosmotic because of
diffusion of water out of the blood and diffusion of
solutes from the renal interstitial fluid into the
blood.
 In the ascending limb of the vasa recta, solutes
diffuse back into the interstitial fluid and water
diffuses back into the vasa recta. Large amounts of
solutes would be lost from the renal medulla
without the U shape of the vasa recta capillaries

Vasa Recta : CC Exchanger Role of Urea

 urea contributes about 40 to 50 per cent of the
osmolarity (500-600 mOsm/L) of the renal
medullary interstitium when the kidney is forming
a maximally concentrated urine.
 Unlike sodium chloride, urea is passively
reabsorbed from the tubule, through transporters
 There are at least four isoforms of the transport
protein UT-A in the kidneys (UT-A1 to UT-A4);
UT-B is found in erythrocytes

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Renal Innervation
 The amount of urea in the medullary interstitium  The renal nerves travel along the renal blood
and, consequently, in the urine varies with the vessels as they enter the kidney. They contain many
amount of urea filtered, and this in turn varies with postganglionic sympathetic efferent fibers and a
the dietary intake of protein. Therefore, a high- few afferent fibers.
protein diet increases the ability of the kidneys to  There also appears to be a cholinergic innervation
concentrate the urine via the vagus nerve, but its function is uncertain.

 The sympathetic preganglionic innervation comes  In addition, there is a dense noradrenergic

primarily from the lower thoracic and upper lumbar innervation of the thick ascending limb of the loop
segments of the spinal cord, and the cell bodies of of Henle
the postganglionic neurons are in the sympathetic  Nociceptive afferents that mediate pain in kidney
ganglion chain along the renal artery disease parallel the sympathetic efferents and enter
 The sympathetic fibers are distributed primarily to the spinal cord in the thoracic and upper lumbar
the afferent and efferent arterioles, the proximal dorsal roots
and distal tubules, and the juxtaglomerular

33