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Preface

Dear Medicos,
Agam Medical Organization has been dedicated to fostering a culture of academic
excellence and knowledge sharing among medical students. Our organization has always
recognized the importance of passing on the torch of learning to the next generation. Today,
we are proud to present the culmination of years of dedication and hard work: the Agam
Medical Organization's Physiology Study Material.
This comprehensive study material is not just a book; it's a testament to the spirit of
collaboration and the unwavering commitment of our fellow students to their academic
pursuits. As we navigate the challenging journey of medical education, we understand the
significance of having reliable and concise resources at our disposal. This study material has
been meticulously crafted with this understanding in mind.
The material within these pages is the result of countless hours of research, study group
sessions, and the collective wisdom of our seniors. It has been designed to aid you in
comprehending the intricacies of physiology and, more importantly, to empower you to excel
in your undergraduate university exams.
Each chapter within this book delves into various aspects of physiology, offering not just
theoretical knowledge but also practical insights. We have strived to simplify complex
concepts, making them accessible to all readers, regardless of their level of familiarity with
the subject.
Furthermore, we have incorporated summaries, and diagrams to facilitate effective revision.
We firmly believe that learning should be a dynamic process, and this study material
encourages active engagement with the subject matter.
As you embark on your journey through the pages of this book, remember that you are not
alone. You have the collective wisdom and support of Agam Medical Organization and its
members behind you. We are here to help you succeed.
We extend our heartfelt gratitude to all the contributors, without whom this project would not
have been possible. Their dedication and passion for the subject shine through in every page.
We hope that this Physiology Study Material serves as a valuable companion on your
academic path, guiding you toward a deeper understanding of the human body and fostering a
love for the subject. May it be a beacon of knowledge that illuminates your path to success.

Best wishes,
Agam
Acknowledgment

In the journey of creating the Agam Medical Organization's Physiology Study Material, we
have been fortunate to receive support, guidance, and inspiration from numerous sources. We
would like to extend our heartfelt gratitude to:

Contributors:
We are deeply appreciative of all the individuals who contributed to this material, whether
through research, content creation, or editorial work. Your collective efforts have resulted in a
resource that will benefit countless students. A special thanks to Jwala S, for leading the team
to bring the material in perfect form. We would like to express our deepest appreciation to:
Suba Vishnu Durga. A
Thavansree D
R. Kirushika
Haritha
Jwala S
Jothika
God:
We begin by expressing our gratitude to the Almighty for bestowing upon us the wisdom,
strength, and determination to undertake this endeavour.

Pioneers in the Field of Physiology:

We stand on the shoulders of giants—those pioneering scientists and researchers who paved
the way for our understanding of the human body's intricate workings. Their dedication to
advancing the field of physiology has been our guiding light.

Doctors and Professors:

To the medical professionals and educators who have tirelessly imparted their knowledge and
expertise to generations of students, we owe a debt of gratitude. Your dedication to teaching
and healing has inspired us to strive for excellence.

Seniors:
A heartfelt thanks to our senior colleagues who generously shared their wisdom and
experiences with us. Your mentorship and guidance have been invaluable in shaping this
study material.
Supportive Families and Friends:
Behind every student is a network of family and friends who offer unwavering support. We
thank our loved ones for their patience, encouragement, and understanding throughout this
journey.

The entire Agam Medical Organization:

To our dedicated members and the organization itself, thank you for providing a platform
where students can collaborate, learn, and grow together. Your commitment to knowledge-
sharing is the driving force behind this initiative.

Fellow Students:
Last but not least, we extend our gratitude to our fellow students who will use this study
material. It is for you that we embarked on this journey, and we hope that this resource
empowers you to excel in your academic pursuits.

This study material is a testament to what can be achieved through collective effort and a
shared passion for learning. As we move forward, let us remember the importance of giving
back and supporting one another in our pursuit of knowledge.

With sincere thanks,

Agam
 CONTENTS
ESSAY:
1. Define GFR and describe about the factors that regulate Pg No: 3
GFR. Add a note on measurement of GFR

2. Explain about the counter current mechanism in Pg No: 7

concentration of urine

3. Renal circulation, measurement of RBF, regulation of Pg No: 10

RBF

4. Mechanism of acidification of urine, explain about the Pg No: 13

factors that influence acidification of urine

SHORT NOTES:
1. Juxtaglomerular apparatus Pg No: 19

2. Renin angiotensin system Pg No: 21

3. Tubulo glomerular feedback Pg No: 23

4. Water reabsorption Pg No: 24

5. Diuresis with examples of diuretics Pg No: 27

6. Difference between osmotic and water diuresis Pg No: 28

7. Micturition reflex Pg No: 29

8. Renal clearance Pg No: 30

9. Response of kidney to acid-base disorders Pg No: 31

1
ESSAY

2
 GLOMERULAR FILTRATION RATE
Glomerular filtration rate (GFR) is defined as the amount of filtrate formed by the glomerular
filtering membrane of both kidneys in a unit time. Normally, it is 125 mL/min (7.5 L/h or 180
L/day).

Factors affecting glomerular filtration rate: factors affecting renal blood flow,
pressure gradients, glomerular capillary permeability, and surface area of filtration influence
GFR.
1. Renal blood flow: this is the most important determinant of GFR. RBF is directly
proportional to GFR. Renal vasodilation maintains GFR.
2. Capillary permeability: integrity of the glomerular capillary is an important determinant of
GFR. Kf is the product of capillary wall permeability and size of the capillary bed.
● Permeability of the glomerular capillaries is increased in abnormal conditions like
glomerulonephritis and presence of toxic agents. In such conditions GFR is increased,
because plasma proteins are also filtered to a variable degree.
● Decreased capillary permeability occurs due to thickening of capillary membrane in some
diseases leading to decreased GFR.
● Alteration in GFR filtration area of glomerular capillaries can alter the Kf. Mesangial
cells contraction or relaxation is associated with alteration in coefficient of filtration.
● Contraction of mesangial cells leading to decreased Kf is also caused by vasoconstrictors
like angiotensin II, endothelin, norepinephrine, thromboxane A2, leukotrienes C4 and D4
and histamine.
● Relaxation of mesangial cells leading to increased Kf is caused by vasodilators like
dopamine, cAMP, ANP, nitric oxide (NO) and prostaglandins (PGE).

3. Hydrostatic pressure in bowman’s space fluid: opposes filtration, and therefore GFR is
inversely related to it. It is increased in acute obstruction of urinary tract (e.g., a ureteric
obstruction by stone).
4. Glomerular capillary hydrostatic pressure: GFR is directly related to PGC. Changes in
PGC serve as a primary means for physiological regulation of GFR. PGC is mainly dependent on
arterial pressure, renal blood flow, afferent arteriolar resistance and efferent arteriolar resistance.
● Arterial pressure. GFR is auto regulated between arterial pressure of 80 to 200 mmHg.
Increased arterial pressure above 200 mmHg may raise GFR and decreased arterial
pressure below 70 mmHg may lower GFR.
● Renal blood flow: GFR is directly proportional to the renal blood flow. However, renal
blood flow is controlled by auto regulatory mechanisms.
● Afferent and efferent arteriolar resistance: Decreased renal vascular resistance increases
the Renal blood flow in turn increases the GFR and vice versa.
● In acute renal failure, GFR declines because of fall in PGC.

3
5. Glomerular capillary oncotic pressure (πGC). GFR is inversely proportional to πGC. In
hyperproteinaemia and in Hemoconcentration ratio, the πGC is raised leading to decrease in
GFR. Conversely, in hypoproteinaemia and haemodilution the πGC is reduced leading to
increased GFR.
6. Sympathetic stimulation: GFR decreases in exercise due to sympathetic stimulation that
causes more afferent arteriolar constriction than constriction of efferent arteriole. Also,
maintaining body in standing position for a longer duration decreases GFR due to sympathetic
stimulation.
7. Size, shape and electrical charge of the macromolecule:
● Any substance having molecular weight of <10,000 daltons can be freely filtered by the
glomerular filtration barrier
● Slender and supple molecules can pass easily through the membrane
● Due to the presence of negative charge on the basement membrane, substances with a
negative charge cannot pass through the membrane and get filtered.

MEASUREMENT OF GFR:
Renal Clearance
● Measurement of GFR and RBF is based on the principle of renal clearance. Renal
clearance of a substance is defined as the volume of plasma from which that substance is
completely cleared (removed) per unit time.
● When a substance is removed in urine, a certain volume of plasma is cleared (freed) of
that substance.
● The clearance of a substance can easily be assessed by determining the concentrations of
the substance in plasma and urine, and by estimating the urine flow rate. The formula is
as follows:

Where,
● CX is the clearance of the substance
● UX is the concentration of substance in urine
● V is the urine flow in unit time
● PX is the concentration of substance in the arterial plasma.

Inulin Clearance Test

# Inulin clearance test is commonly used for the assessment of glomerular filtration.

4
# It can be measured by measuring the concentration of the substance in urine and the plasma
concentration of the substance.
# The substance should be freely filtered through the glomeruli and should neither be secreted
nor be reabsorbed by the tubules.

Where,
● UX is the concentration of substance in urine
● V is the urine flow in unit time
● PX is the concentration of substance in the arterial plasma.
As the substance is not metabolized in the body the concentration in the venous plasma can be
taken for the concentration in arterial plasma. This value of GFR is called the clearance of the
substance (CX).

Criteria of the substance used:

1. It should be freely filtered by the glomeruli.
2. It should be neither reabsorbed from nor secreted in the renal tubules.
3. It should not be synthesized or stored or altered in the kidney.
4. It should not be metabolized in the body.
5. It should be non-toxic to the body.
6. Its concentration in plasma and urine should be easily measured.
The substance usually used is inulin, a polymer of fructose, as it meets all the criteria of an
ideal substance for measuring GFR.
It is injected intravenously initially as a bolus dose and then through continuous infusion to
maintain a constant concentration in the arterial plasma. Once, inulin equilibrates with body

fluids, the urine and plasma sample are collected for its estimation.
For example, if the urine concentration is 40 mg/mL, the plasma concentration is 0.25 mg/mL,
and rate of urine flow is 0.8 mL/min. Then:

As inulin is neither reabsorbed nor formed, altered, and stored in the kidney, the filtered load of
inulin equals the rate of inulin excretion. Therefore, inulin clearance equals the GFR.

5
Creatinine Clearance Test
#Endogenous creatinine clearance is used clinically to estimate GFR.
#Creatinine is the end product of creatinine phosphate, a skeletal muscle derivative.
#It is produced continuously in the body and excreted continuously in urine.
#Therefore, the concentration of creatinine in plasma and urine are normally stable.
#Its concentrations are measured in plasma and urine and the urine flow rate is (volume of urine
formed per unit time) determined.
#Then, creatinine clearance is calculated as

#The advantages are that no infusion of creatinine is required

6
 COUNTER CURRENT MECHANISM IN FORMATION OF
URINE
● The mechanism by which urine is concentrated is known as counter-current mechanism
● In medulla, there is an increasing gradient of osmolality from outer region to inner
region, highest osmolality is at the tip of the renal papillae
● The osmolality is maintained by the counter current mechanism which is an essential part
of urine formation
● Countercurrent means flow of fluid in opposite directions

Requirements:
● 2 tubes that lie parallel
● The fluid flow should be opposite
● Tubes should be in close proximity
● Should be selectively permeable

In the kidney, there are 3 countercurrent processes that take place:

● Countercurrent multiplier: done by the loop of Henle, this establishes an osmotic gradient
in the medulla
● Countercurrent exchanger: done by the vasa recta, this maintains the osmotic gradient in
the medulla by passive exchange of solutes
● Equilibrating device: done by the collecting duct that is near the vasa recta and LOH

7
Countercurrent multiplication system:
This is the process by which a small osmotic gradient established at any level of LOH is
multiplied into a larger gradient.
The osmotic gradient at any level is called single effect, which is caused by the movement of
solutes out of the ascending LOH that is impermeable to water
Axial gradient: along the axis of the loop, as the loop enters the deeper layers, there is an
increase in osmolality. This is influenced by 3 main factors
🡺 Rate of fluid flow
🡺 Strength of single effect
🡺 The length of LOH
Steps:
1) Flow of fluid to the medulla until it reaches the tip of LOH
2) Fluid moves to the ascending limb
3) Solutes in this region move out and accumulate in interstitium as ascending LOH is
impermeable to water
4) If water is present in the interstitium, it is removed by the vasa recta
5) Additionally, urea in the collecting duct also diffuses out to reach the interstitium to
increase the osmolality

8
Counter current exchange:
● It is maintained by the vasa recta
● The exchange of solutes and water takes place passively and this process decreases the
dissipation of gradient from the medulla
● Water is removed by the descending limb of vasa recta which is taken up by the
ascending limb of vasa recta
● There is a constant exchange of water and solutes between both the limbs of vasa recta
that maintain the medullary osmolality
● The movement of water is opposite to the movement of solutes
● In the descending limb, solutes diffuse into the vessel, in the ascending limb solutes
diffuse out of the vessel

Role of collecting duct:

Collecting duct contributes to urine formation in 2 ways
🡺 Collecting duct is permeable to water so water mooves out of the tubular fluid in the
interstitium and is taken up by the collecting duct
🡺 Some part of the urea transported into the collecting duct is secreted into the tubular fluid
in the descending limb of LOH as the medullary part of collecting duct is somewhat
permeable to urea. Urea passively moves along with water from the interstitium that
helps to maintain osmotic balance

Applied aspect:
The amount of protein controls the urine concentration. Urea amount depends on the amount of
protein consumed.

9
 RENAL BLOOD FLOW, REGULATION, MEASUREMENT
🡺 Kidneys receive about 2.35% of the cardiac output
🡺 The blood flow rate in cortex is 5ml/min/g and 0.5ml/min/g in the medulla
🡺 The low blood flow in medulla is important to maintain the hyperosmolality in the
interstitium

Blood supply of kidney:

🡺 Arterial: renal artery 🡪 anterior and posterior division 🡪 5 segmental arteries🡪 interlobar
artery🡪 arcuate artery 🡪 interlobular artery 🡪 afferent arteriole 🡪 glomerular capillary
network
🡺 Venous drainage: efferent arteriole 🡪 peritubular capillaries 🡪 arcuate veins 🡪 interlobar
veins 🡪 segmental veins 🡪 renal vein

10
Importance of renal blood flow:
🡺 Supplies oxygen, nutrients and hormones that control kidney functions
🡺 Delivers metabolites and waste products for excretion
🡺 Controls concentration and dilution of urine
🡺 Influences solute and water reabsorption from kidney
🡺 Determines GFR and is the main determinant

Principle of measurement of RBF:

Fick’s principle is the major governing principle: the amount of a given substance taken up by
the organ per unit time is proportional to the arteriovenous difference of the substance across the
kidney
Criteria of substance:
🡺 Should be measurable in arterial and venous blood
🡺 Should not be metabolized
🡺 Should not be stored
🡺 Should not be produced by the kidney
🡺 Should not affect the blood flow by itself
The most ideal substance for measuring RBF is para-amino hippuric acid (PAH)

First, RPF should be measured. It can be measured by injecting PAH and determine the
concentration of PAH in urine and plasma.
The extraction ratio for PAH is high
RPF is calculated by dividing the amount of PAH in urine by the plasma levels of PAH. This
value is called the effective renal plasma flow.

11
Regulation of RBF:
Neural factors:
🡺 Sympathetic control: vasoconstriction that decreases RBF
🡺 Conditions that activate sympathetic response like hemorrhage, cold, pain, exercise,
anesthesia decrease blood flow to the kidney
🡺 Angiotensin 2 formation and sympathetic stimulation to kidneys stimulate the production
of local hormones like PGE2 and PGI2 that produce vasodilation and oppose
vasoconstriction effects.

Hormonal factors:
🡺 Dopamine in high dose can cause renal vasodilation
🡺 It is the preferred treatment for cardiogenic shock

Local factors:
🡺 CO2 and PGs produce vasodilation
🡺 Adenosine causes vasoconstriction in renal vascular bed

Autoregulation:
Myogenic mechanism:
🡺 Renal autoregulation of blood flow is an intrinsic phenomenon
🡺 The autoregulation is mainly due to the direct contractile response of the renal smooth
muscle of afferent arteriole to stretch.
🡺 Increased pressure causes opening of cation channels that result in depolarization,
🡺 This leads to voltage dependent influx of Ca that causes vasoconstriction

Metabolic mechanism:
🡺 Local secretion of PGs, adenosine, NO influence the blood flow

Glomerulo tubular feedback:

🡺 The composition and flow of tubular fluid determine the RBF and glomerular filtration.

12
 MECHANISM OF ACIDIFICATION OF URINE
The kidney is an important organ in maintaining the acid base balance of the body.
It excretes the excess acid from the body, thereby preventing acidosis in the body

ACIDIFICATION IN PROXIMAL TUBULE

● CO2 combines with H2O to form carbonic acid

● This carbonic acid dissociates to form HCO3- and H+ ions, that dissociates with the help
of carbonic anhydrase
● The H+ ions enter the tubular lumen with the help of a Na-H antiport and the HCO3
diffuses into the interstitium.
● The acidification of urine in PCT is dependent on the Na concentration in the tubular
fluid.

Effects of parathormone and carbonic anhydrase:

● Parathormone inhibits Na+-H+ exchanger in apical cell membrane of PCT and therefore
affect pH
● As carbonic anhydrase plays a vital role in PCT, drugs that inhibit its action decrease the
acidification of urine

13
ACIDIFICATION IN DISTAL TUBULE AND COLLECTING DUCT

● Aldosterone increases distal tubular acid secretion by acting on these pumps directly.
● I cells of DCT are equivalent to the parietal cells of stomach as they actively secrete acid.
These cells are rich in carbonic anhydrase
● Band 3 protein, an anion exchanger protein located at the basolateral membrane acts as
chloride-bicarbonate exchanger
● H+-K+ ATPase to some extent secretes H+ and absorbs K+ in the collecting tubule

FURTHER MODIFICATIONS IN ACIDIFICATION

● IN PCT

● The bicarbonate ion

after it diffuses into the

14
 interstitium reaches a concentration of 24 mmols.
● This is an effective buffer that forms CO2 and breaks down to form acid again that
diffuses into the tubular lumen for excretion.

IN DCT AND COLLECTING DUCT

● In the DCT, the phosphate buffer is more effective.

● The secreted acid reacts with dibasic phosphate buffer to form monobasic phosphate.
● The monobasic phosphate is excreted and Na is reabsorbed
● In DCT and collecting tubules, the phosphate gets concentrated due to the absorption of
water, hence this is an even effective buffer.

IN PCT AND DCT:

● The ammonia buffer plays an important role.
● The ammonia through a transporter diffuses into the tubular fluid where it reacts with the
acid to form ammonium ion, that is subsequently excreted.
● This serves as an important route to create a constant gradient for further ammonia
diffusion. This is also called as nonionic diffusion
● This is an important pathway used in metabolic acidosis

15
FACTORS AFFECTING ACIDIFICATION OF URINE
Four important factors contribute to acidification of urine:
1. Renal acid excretion
2. Renal bicarbonate reabsorption
3. Acid-base status of the body
4. Other factors (mainly hormonal)

RENAL ACID EXCRETION:

● Kidney contributes to acid-base balance by excreting acid, which is proportionate to the
production of non-volatile acids in the body. Kidney also prevents bicarbonate loss
● Most of the H+ secreted into the tubular fluid, which is about 4400 meq/day, serves to
reabsorb the filtered HCO3–, and only about 100 meq/day is excreted in urine. Therefore,
normally urine is mildly acidic.

RENAL BICARBONATE REABSORPTION

● Amount of bicarbonate reabsorbed from tubular fluid equals the amount filtered.
Therefore, under normal conditions, HCO3– is not excreted in urine.
● About 80% of the total filtered bicarbonate is reabsorbed in PCT and 15% in thick
ascending limb of LOH and 5% in the collecting duct
● The mechanism of bicarbonate reabsorption in PCT involves Na+-H+ antiporter in the
apical surface of the epithelial cells
● In the thick part of ascending limb of LOH, mechanism is similar to that in the PCT.
● In DCT and collecting duct, reabsorption does not require Na+-H+ antiporter.

ACID BASE STATUS OF THE BODY

● In metabolic acidosis, acidification of intracellular fluid increases H+ gradient between
tubular cell and lumen. This results in increased H+ secretion.
● In metabolic alkalosis, HCO3 − reabsorption as well as acid secretion from kidney is
decreased thereby causing a decrease in urine acidification rate. In metabolic alkalosis,
when plasma bicarbonate level goes beyond 28 mmol/L, renal threshold for bicarbonate
reabsorption crosses its limits and the bicarbonate ions start appearing in the urine.
Hence, urine acidification drops down.
● In respiratory acidosis, when pCO2 increases, the H+ formation increases by the action
of carbonic anhydrase. This causes increased reabsorption of bicarbonate and
acidification of urine.
● The reverse happens in case of respiratory alkalosis.

16
OTHER FACTORS
● Aldosterone, parathormone, angiotensin II and plasma K+ contribute to acidification of
urine.
● Aldosterone increases H+ secretion from the tubular cells into the tubular fluid.
Therefore, it contributes to urine acidification and alkali reabsorption in the kidney.
● Angiotensin II secondarily affects Na+ concentration and Na+-H+ exchange, hence
affects urine acidification

17
SHORT NOTES

18
 JUXTAGLOMERULAR APPARATUS
The juxtaglomerular apparatus is formed when the loop of Henle comes in contact with the
glomerulus of the same renal corpuscle.
The entire modified structure is called the juxtaglomerular apparatus (JGA) that includes:
● the extraglomerular mesangial cells.
● the macula densa.
● the granular cells.
The JGA is part of a complex feedback mechanism that regulates renal blood flow and filtration
rate and it also indirectly modulates Na+ balance.

Mesangial cells:
● They are also called as Lacis cells.
● They are found in a triangular space formed by the efferent and afferent arterioles and the
macula densa.
● Help in the regulation of glomerular filtration. They also secrete extracellular matrix
● Mesangial cells are especially common between two neighbouring capillaries.
● They are agranular cells that secrete some quantities of renin and erythropoietin.

The macula densa:

● Region of specialized modified epithelial cells of the thick ascending limb, where it
contacts its glomerulus between afferent and efferent arterioles.
● The terminal portion of the thick ascending limb of LOH that passes through the angle
formed by the afferent and efferent arterioles of the same nephron posses this tubular
epithelial modification that appears as a dense area, hence called macula densa as the
epithelial cells are closely packed in this region.
● They act as the sensor that monitor the change in ionic composition and rate of flow of
the tubular fluid in the lumen of the tubule.
● It provides feedback signal to the renal corpuscle to change the rate of filtration to meet
the need of kidney functions.
● It is an important component of the tubuloglomerular feedback.

The juxtaglomerular cells:

● Also called as epithelioid cells or Polkissen cells.
● They are present in the tunica media of the afferent arteriole that come in contact with the
terminal part of the thick ascending limb of LOH.

19
 ● They are modified vascular smooth muscle cells with an epithelioid appearance.
● They contain many secretory granules and are responsible for secreting and storing renin
that activate the renin angiotensin system.

Functions of JG apparatus:
● Activate the renin-angiotensin system that is involved in the regulation of blood volume
and pressure
● Macula densa acts as a sensor that detects the change in the rate of flow and volume of
flow in the tubule, which provides a feedback signal to the glomerulus is the
physiological basis of tubuloglomerular feedback
● Lacis cells secrete renin and erythropoietin.

20
 RENIN-ANGIOTENSIN SYSTEM
● The renin-angiotensin system is a mechanism by which blood volume and pressure are
regulated.
● The main trigger is the release of renin from the JG apparatus that takes part in further
actions.

Renin:
● It is an acid protease that is secreted from the JG cells of the kidney.
● It is responsible for the conversion of angiotensinogen to angiotensin 1 which is further
activated.
● Conditions like hypovolemia, hemorrhage, hypotension, and hyponatremia act as
triggers for the release of renin
● Sodium is an important electrolyte that controls renin secretion.

Angiotensin-2:
● This is the most important of all angiotensins that acts via angiotensin receptors AT1 and
AT2
● It is a potent vasoconstrictor, but the action decreases in conditions like liver cirrhosis and
hyponatremia
● It increases the synthesis and secretion of aldosterone from the adrenal cortex that aids in
sodium and water reabsorption.
● It directly stimulates the release of norepinephrine from the post ganglionic sympathetic
neurones and causes contraction of mesangial cells

Clinical importance of RAAS:

● RAS is implicated in the genesis of hypertension that forms the most important
physiological basis of renal hypertension
● Goldblatt hypertension: renal hypertension produced by constriction of renal artery
● Hypertension can be classified as normo renin, hyper renin and hypo renin hypertension
● ACE inhibitors and ARBs (angiotensin receptor blockers) are the first line treatment for
hypertension

21
22
 TUBULOGLOMERULAR FEEDBACK:
Signals originating from the renal tubule provide feedback for the control of glomerular filtration
The rate and flow of concentration of NaCl in the distal part of thick ascending loop of Henle is
an important feedback mechanism
The change in glomerular filtration maintains a constancy of tubular load
The most important sensor is the macula densa that is an important part of juxta glomerular
apparatus

Steps:
Macula densa acts as a sensor

Senses the rate of flow of tubular fluid and the NaCl content

If there is more NaCl, they will enter through the Na-K-2Cl transporter in the macula densa cells

Increase Na-K ATPase activity

Formation of adenosine

Release of Ca from macula densa

Constriction of afferent arteriole

Decreased glomerular filtration

Feedback regulation of GFR

Applied aspect:
Tubulo glomerular feedback of renal blood flow plays a very important role in autoregulation of
renal blood flow to maintain the pressure between 80-180 mmHg

23
 WATER REABSORPTION
The volume of urine excreted is determined by the quantity of water reabsorbed from renal
tubule.
Kidneys reabsorb more than 99% of the filtered water, which is a major mechanism of volume
homeostasis of the body.

TYPES OF WATER REABSORPTION

Water reabsorption in renal tubules is of 2 types
Obligatory Reabsorption Facultative reabsorption

Water reabsorption that occurs secondary to Water absorption that occurs secondary to the
reabsorption of solutes. effects of hormones (ADH, aldosterone).

This accounts for about 85%of total water This accounts for about 15% of total water
reabsorption reabsorption from the kidneys.

MECHANISM OF WATER REABSORPTION

● In Proximal Convoluted Tubule

About 65 % of filtered water is reabsorbed here.
1. The driving force is transcellular osmotic gradient, established by absorption of sodium ions
and accompanying solutes.
2. Due to presence of aquaporins 1, the permeability of PCT is extremely high
3. Small amount of water also passes through water channels present in paracellular route,
through tight junctions between epithelial cells

● In Loop of Henle
Nearly 15% of filtered water is reabsorbed here.
1. Ascending limb of LOH is impermeable to water and water reabsorption occurs mainly in
descending limb
2. It is a passive process that occurs secondary to higher osmolarity of medullary interstitium.

● In Distal Convoluted Tubule

It is relatively impermeable to water. Only 5% of water reabsorption takes place in DCT, which
is influenced by ADH and aldosterone

24
 ● In Collecting Duct
1.Reabsorption of both solute and water depends on concentration of ADH acting on collecting
duct.
2.About 12 to 25% of water is reabsorbed in CD.
Collecting duct has 2 parts
● Cortical CD
In the presence of ADH there is substantial reabsorption of water.

ADH binds to V2 receptors of tubular cells

Activation of adenylate Cyclades

Increase production of cAMP

Activation of protein kinase A

Increased water permeability

● Medullary CD
In this part water is reabsorbed along the osmotic gradient that accounts for 5 – 10% of water
reabsorption. This plays an important role in countercurrent mechanism and makes the urine
concentrated.

Applied aspects
Nephrogenic diabetes insipidus is characterized by decreased expression of aquaporin 2 in
collecting duct and distal convoluted tubule.

25
26
 DIURESIS
Diuresis is a condition where urine output is increased. It occurs due to failure of mechanisms
that concentrates urine.
Diuresis is categorised into 2 types : Water diuresis and Osmotic diuresis.

DIURETICS
Diuretics are substances which enhance the output of urine. These substances increase the
excertion of water, sodium, chloride through urine.
Diuretics are usually used to decrease the ECF volume and blood pressure.

Class of diuretics Mechanism of action Site of action

Osmotic diuretics (mannitol, Inhibit water and solute proximal tubules

glucose, sucrose) reabsorption by increasing
osmolarity of tubular fluid

Loop diuretics (furosemide, Inhibit Na-K-Cl cotransporter Thick ascending loop of

bumetanide) Henle

Thiazide diuretics Inhibition of Na-Cl cotransporter early part of distal

(chlorothiazide, (hence increased NaCl secretion) tubules
hydrochlorothiazide)

Carbonic anhydrase inhibitors Inhibit H+ secretion and HCO3 Proximal tubules

(acetazolamide) reabsorption. Hence reduced Na
reabsorption

Aldosterone antagonist K+ sparing diuretics. Inhibits Collecting Duct

(spironolactone, eplerenone) action of aldosterone on tubular
receptors and decreases Na
reabsorption

Sodium channel blockers Blocks Na channels and decrease Collecting ducts

(triamterene, amiloride) its reabsorption. Decrease
secretion of K ions

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Site of action of various diuretics 1. Loop diuretics 2.Thiazides 3.Aldosterone antagonist
4.Antagonist to V2 vasopressin receptors

WATER DIURESIS AND OSMOTIC DIURESIS

Diuresis is the excess excretion of water in urine.
Diuresis is classified into 2 broad categories - water diuresis and osmotic diuresis

WATER DIURESIS OSMOTIC DIURESIS

It is the excretion of large volume of water Increase in excretion of water due to

without loss of excess of solutes. increased concentration of osmotically active
particles in tubular fluid.

This occurs when the capacity of tubules to This occurs when osmolality of tubular fluid
reabsorb water is impaired. is more

Seen in ADH Deficiency like in diabetes Typically seen in diabetes mellitus. Due to
insipidus, where urine is dilute and more in increased glucose load on tubules, solute
volume. holds water and prevents its reabsorption from
the tubules.

It can be physiologically demonstrated by This can be produced by administration of

drinking a large amount of hypotonic fluid mannitol, and also by infusion of large
like water (polyuria occurs in 15-40 minutes amounts of NaCl or urea.
of ingestion)

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 MICTURITION REFLEX:
● It is the process of passing urine.
● This is a reflex phenomenon that is integrated in the spinal cord.
● This is influenced by the activity of the higher centres.
● Unless the bladder is filled, urine accumulates in urinary bladder without much increase
in the intravesical pressure, this property is called plasticity
● Due to plasticity, tension produced by the stretching is not maintained. This relationship
between the bladder volume and the pressure is best studies by cystometry.

MECHANISM:

⬇️
Bladder volume (450ml)

⬇️
Bladder stretches

⬇️
Stretch receptors activates

⬇️
Impulse sent to sacral centres (S2, S3,S4) via parasympathetic centres

⬇️
Impulse relayed to detrusor

⬇️
Internal sphincter relaxes

⬇️
Stretch receptors activated further

⬇️
Increases impulse traffic to and from spinal centre

⬇️
Stronger contraction of the bladder muscle making the reflex process stronger

⬇️
Urine pushed into urethra

⬇️
Afferent through pudendal nerve to sacral centre

⬇️
Inhibition of pudendal nerve to the external urethral sphincter

⬇️
Relaxation of external urethral sphincter

Passage of urine

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Applied aspect:
Abnormalities of micturition:
The lesions at different segments of the neuraxis result in bladder dysfunctions.
There are 3 major neural defects that produce bladder dysfunctions
● De-afferentation: results in hypotonic and thin bladder, seen in tabes dorsalis
● Denervation: leads to flaccid and distended bladder, seen in denervation hypersensitivity
of the bladder
● Spinal cord transection: phase of shock, recovery and failure; micturition reflex is the 1st
to return in the phase of recovery,

RENAL CLEARANCE

Definition:
Renal clearance of a substance is defined as the volume of plasma from which that substance is
completely removed from plasma per unit time

Cx =Ux *V /Px

● Cx: clearance of the substance

● Ux: concentration of substance in urine
● V: urine flow in unit time
● Px: concentration of substance in the arterial plasma

Criteria of the substance used:

● It should be freely filtered by the glomerulus

● It should be neither reabsorbed from nor secreted in the renal tubules
● It should not be synthesized or stored or altered in the kidney
● It should not be metabolized in the body
● It should not be toxic to the body
● Its concentration in the plasma and urine should be easily measured

Inulin clearance test:

Inulin meets all the above criteria and hence used as an ideal substance for measuring GFR

GFR =Ux *V /Px , this value of GFR is called the Clearance of the substance(Cx)

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Here inulin given as bolus dose and the plasma concentration maintained by continuous
infusion….

For ex, if Ux =40 mg/ml

Px =0.25 mg/ml
V =0.8ml/min…. then by applying formula,

Cx =128ml/min….as seen above the filtered inulin equals rate of inulin excretion.
Inulin clearance equals GFR

Creatinine clearance test:

Creatinine is an endogenous skeletal muscle derivative. Its concentration in plasma and urine
used to measure creatinine clearance.

RESPONSE OF KIDNEY TO ACID BASE DISORDERS

Respiratory Acidosis:

⬇️Ventilation
⬇️
⬆️ Arterial PCO2 and CO2
⬇️
⬆️H+ ions formed.
In this case the kidney facilitates:
1. H+ secretion
2. HCO3- and Na+ reabsorption
3. Excretion of Cl-
4. Ammonia secretion, which can tie up more H'ions in the lumen.

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Respiratory Alkalosis:
There is a fall in the arterial PCO2 and CO2 level as CO2 is washed out due to hyperventilation
either voluntarily or in
respose to hypoxia. Now CO2 is formed from HCO3-.
In this case,H+ ion formation is less. Therefore,
1. H+ secretion is less.
2. Filtered HCO3- is excreted
3. Na+ absorption is accompanied by Cl-
4. K+ excretion increases.

Renal Compensation in Metabolic Acidosis and Alkalosis

When acids stronger than Hb and other buffer acids are added to blood, metabolic acidosis is
produced.
When the free H+ level falls as a result of addition of alkali or removal of acid, metabolic
alkalosis results.

Metabolic Acidosis :
Seen in
-diabetic ketosis
- lactic acidosis
- uraemic acidosis
- diarrhoea.
The rise in plasma H+ stimulates respiration, so that CO2 is eliminated and H2CO3 level falls.
Plasma HCO3- is also reduced. The kidneys filter the acid anions that replace HCO3- in plasma
each with a cation, mainly Na+.
H+ ions are secreted into the luminal fluid. For each H+ ion secreted, one Na and HCO3- are
reabsorbed so that more HCO3- is added to blood.
1. Na and HCO3- are reabsorbed.
2. Acid causing anions like CI-, SO4-, and PO4-, are excreted.
3. NH3 is secreted.
4. H+ ions are secreted.

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Metabolic Alkalosis:
Seen in
-prolonged vomiting
-treatment with diuretics.
As the acids are lost, H+ concentration decreases. This inhibits respiration, so PCO2 gradually
rises and pH is brought down to the normal level. In metabolic alkalosis as in vomiting:

⬇️
1. HCO3- is excreted into urine.
2. H+ secretion
3. Increase in Cl- HCO3, exchange, i.e., Cl- is absorbed and HCO3-, excreted.
4. K+ is secreted.

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