Unit

The Excretory System

7
Physiological Anatomy of the kidney
Kidney Structure (Fig. 7.1)

n
Nephron: Functional unit; 1-1.3 millions/kidney; total length: 45-65 mm.

i
Note: Kidney dysfunction do not occur until functional nephrons falls < 25%)

J a Left kidney
(in vertical-section)

.
Cortex
Renal artery
Kidney and Vein
Medulla

K
Ureter
Urinary Renal papilla

.
bladder Hilus Minor calyce

A
Renal capsule

Ureter
Major calyce
Renal pelvis

Fig. 7.1 Structure of the kidney

Different parts (Fig. 7.2)

1. Bowman’s capsule: initial dilated part
2. Glomerulus – tuft of capillaries, supplied by afferent and efferent arterioles.
(1) and (2) together constitute Malpighian corpuscle.
Organization and functions of glomerulus
(i) Visceral cell layer
(ii) Parietal cell layer
(space between (i) and (ii) ­– Bowman’s space)
(iii) Glomerular membrane (or glomerular capillary wall) – Total area: 0.8 m2
Structure: made of 5 layers.
(a) Layer 1: Visceral epithelial cell layer.
(b) Layer 2: Overlying foot processes of podocytes.

1
 2

Afferent arteriole

Efferent arteriole
Capillary
Fenestration (pore)
F
Plasma Capillary i
Squamous epithelial cells l
endothelium
of Bowman's capsule t
(Parietal cell layer) Basement r
membrane a
Glomerular epithelium t
(Visceral cell layer) Silt diaphragm i
o
Bowman's space n
Filtration

n
slit
m

i
Glomerular capillary plexus Foot processes e
Filtrate in of podocyte m
capsular space of glomerular b
capsule r

a
a
Cells of PCT n
Three parts of the filtration membrane
e

J
Fig. 7.2 Organization of the glomerulus

(c) Layer 3: The basement membrane.

.
(d) Layer 4: Provides bed for capillary endothelium.
(e) Layer 5: Endothelial cell layer of glomerular capillaries.
(iv) Glomerular capillaries

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(a) each capillary contains 20-40 capillary loops;
(b) exhibit higher pressure, 45 mmHg;

.
(c) it produces an Ultrafiltrate; free passage of neutral substances upto 4 nm in diameter.
3. Proximal convoluted tubule (PCT) – responsible for active transport of substances
(i) consist of numerous microvilli → +++ ↑ surface area for absorption;

A
(ii) 2 parts: pars convoluta and straight part pars recta.
4. Loop of Henle: descending limb, thin segment and thick ascending limb (L: 12 mm).
5. Distal convoluted tubule (DCT): modified to become columnar (Macula densa) and with the afferent
arteriolar wall form juxta glomerular apparatus.
6. Collecting Tubules (CT): Its epithelium 2 types of cells:
(i) P (principal) cells → of CT.
(ii) I (intercalated) cells.

Types of Nephrons (Fig. 7.3)

Cortical Nephrons Juxta-Medullary Nephrons

1. Comprise 85% of total nephrons. 1. Comprise 15% of total nephrons.

2. Smaller size glomeruli located in the renal 2. Larger size glomeruli located at the cortex and
cortex. medulla junction.
3. Short loops of Henle. 3. Long loops of Henle (penetrate deep into the
medulla).
4. Descending limb loop of Henle (thin) segment 4. Both limbs of loop of Henle thin.
ascending limb (thick) segment.
5. Henle’s loop vascular supply peritubular capillary 5. Vasa recta.
plexus.
6. Rate of filtration: slow. 6. High.
7. Play a major role in excretion of waste 7. Countercurrent system → concentrate urine.
products.
  7: The Excretory System ❑ 3

Distal convoluted
tubule
Afferent arteriole
Efferent arteriole
Cortex
Proximal
convoluted
tubule

Peritubular Outer
capillary medulla
plexus
Loop of Henle
Renal artery Inner

n
medulla
Renal vein

i
Vasa

a
recta

J
Fig. 7.3 Cortical nephron (Left) and Juxta-medullary
nephron (Right)

.
Juxta Glomerular Apparatus (JGA)

K
A. Components (Fig. 7.4)

.
1. Juxta glomerular cells (JG cells)
(i) modified vascular smooth muscle cells in the afferent arterioles;
(ii) release a proteolytic enzyme–Renin;
(iii) baroreceptors;

A
(iv) innervation: sympathetic constrictor nerve;
(v) stimulated by: hypovolemia or ↓ renal perfusion pressure.
Proximal Renal sympathetic
convoluted nerve
tubule

Smooth muscle cells

Capsular
epithelium Afferent arteriole

Juxta glomerular
Capillary
cells (baroreceptors-
loops
releases Renin)

Mesangial (or Lacis)

cells (supporting cells)
Macula densa cells
(chemoreceptors)

Efferent arteriole
Distal convoluted
tubule
Fig. 7.4 Structure of Juxta glomerular apparatus ( JGA)

2. Macula densa cells

(i) modified epithelial cells in DCT; close contact with JG cells, and with both the afferent and
efferent arterioles;
(ii) chemoreceptors;
(iii) stimulated by: ↓ Na+ (NaCl) load → renin release;
(iv) not innervated.
4

3. Mesangial (or Lacis) cells

(i) supporting cells
(ii) contractile → regulate GFR;
(iii) may → renin secretion.

B. Function
Regulate renin secretion.
Regulation of Renin Secretion

Increase Decrease
1. (+) JG cells by: 1. (–) JG cells by:

n
(i) ↑ sympathetic activity (i) ↑ afferent arteriolar P

i
(ii) ↑ Catecholamines (ii) Angiotensin II
(iii) Prostaglandins (iii) ADH
2. Sodium depletion 2. ↑ Na+ and Cl– reabsorption

a
across macula densa.
3. Diuretics 3. ANP

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4. Congestive heart failure –

.
Renin-Angiotensin System
Angiotensinogen (α2 globulin)
↓

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Enzyme-Renin from JGA
Angiotensin I (inactive)

.
↓ ACE (lungs, kidney, plasma)
Angiotensin II
↓

A
ACE (lungs)
Angiotensin III

Actions of angiotensin II
1. Most potent pressor agent DBP (4-8 times more potent than NE).
2. ↑ aldosterone secretion → ↑ Na+ reabsorption.
3. ↑s NE release from sympathetic neurons.
4. Contracts mesangial cells → ↓ GFR.
5. Via circumventicular organs → ↑ thirst, ↑ BP, ↑ ADH and ACTH secretion.

Important Note: Angiotensin III: 40% pressor activity of angiotensin II but 100% aldosterone stimulating
activity.

Kidney Functions
1. Main function: Excrete waste products (e.g. ammonia, urea, uric acid, creatinine, K+ and H+)in the
urine.
2. Homeostatic function by regulating volume and composition of ECF and regulation of acid-base
balance.
(i) by conservation of water: kidneys can normally absorb > 99% of filtrate → forms minimal
(obligatory) volume of the fluid to excrete the waste substances;
(ii) by actively secreting K+ and H+.

Note: Kidneys can concentrate urine upto 5 times the osmolar conc. of the plasma.
  7: The Excretory System ❑ 5

3. Endocrine function: Secrete

(i) Enzyme Renin → helps to regulate BP;
(ii) REF → regulate erythropoiesis;
(iii) Enzyme 1-α-hydroxylase → 1, 25 DHCl → regulate S. Ca2+.
Dietary vitamin D3 (cholecalciferol)
↓ 25 hydroxylase in liver
25 HOCC (hydroxycholecalciferol)
↓ 1-α hydroxylase in kidney
1, 25 DHCC
4. Gluconeogenic function.

n
Blood Supply to the Kidney

i
Important points
1. Afferent arterioles major site of autoregulatory resistance; efferent arterioles have a relatively high

a
resistance.
2. Glomerular capillaries (Fig. 7.5)

J
(i) high pressure (45 mmHg)
(ii) only capillaries that drain into arterioles

.
(iii) total volume of blood: 30-40 mL and TSA: 12m2.
3. Pressure in renal vessels
(i) in glomerular capillaries: 45 mmHg
(ii) in peritubular capillaries: 8 mmHg

K
(iii) in renal vein: 4 mmHg

.
125
Renal Afferent Glomerular Efferent Peritubular Venules
artery arterioles capillaries arterioles capillaries and
renal veins

A
100
Mean Blood Pressure (mmHg)

Constrict
75 efferent
arterioles
Plasma
oncotic
50
pressure

25
Constrict
afferent
arterioles
0

Fig. 7.5 The fall in mean BP across the renal circulation. Note that when the afferent
arterioles constrict, the pressure in the glomerular capillaries falls and when the
efferent arterioles constrict, the pressure in the glomerular capillaries rises.

4. Innervation of renal vessels

(i) sympathetic from T10 to L2 via splanchnic nerves distributed to:
(a) afferent and efferent arterioles
(b) renal tubular cells and JG apparatus
Its stimulation →
(a) ↓ RBF via α1-adrenergic receptors;
(b) ↑ renin secretion via β-receptors;
(c) ↑ reabsorption of Na+ and water.
6

5. Factors affecting RBF

Normal RBF: 1.2–1.3L/min
Decrease by Increase by
(i) catecholamines → renal VC (i) hypertension→ ↓ in symph.activity
(ii) angiotensin II (ii) high protein diet→↑ glo. cap. pressure
(iii) exercise (via ↑ symph. activity) (iii) A-ch → renal VD
(iv) haemorrhage –
(v) posture (from supine to standing)→↓ in BP –

6. Peculiarities of renal circulation

n
(i) Very high: 1.2-1.3 L/min (300-400 mL/100 g/min.

i
(ii) (A–V)O difference low: 19–17.5 = 1.5 mL/dL.
2
(iii) Renal VO very high: 18–20 mL/min
2

a
(iv) Cortical blood flow and VO > medulla. Slow medullary flow → development of hyperosmolarity
2
of the inner medulla → hypertonic urine.

J
Notes: Low medullary blood flow is due to:
1. Vasa recta length (40 times the length of systemic capillaries) → ↑ resistance to blood flow;

.
2. high interstitium osmotic pressure → ↑ viscosity;
3. low hydrostatic pressure head.
4. Advantage: helps development of hyperosomlality of inner medulla and hence for production of hypertonic
urine.

. K
(v) RBF and GFR remain (autoregulated) between 80-200 mmHg MBP (Fig. 7.6).
(a) autoregulation: feature of cortical blood flow;
(b) renal perfusion pressure if ↓s <50 mmHg, the kidney does not filter;

A
(c) autoregulation is due to intrinsic myogenic tone of afferent arterioles.
RBF
1200
80 Autoregulation 200
600
mL/min.

400

200
GFR
125

0
50 100 150 200 250

Mean arterial pressure (mm Hg)

Fig. 7.6 Autoregulation of renal blood flow (RBF) and glomerular

filtration rate (GFR) in kidney

(vi) Autoregulation of RBF and GFR is related to the filtered load of salts, NaCl by Tubulo-glomerular
feedback mechanism.
  7: The Excretory System ❑ 7

Mechanism:

↑ Afferent arteriolar pressure

Inhibit ↑ Glomerular capillary pressure

↑ Glomerular filtration rate

↑ Solute reabsorption in PCT

↑ Fluid delivery to loop of Henle and first part of DCT

n
↑ Na+ and Cl– enty in macula densa cells

i
↑ Na+ — K+ ATPase activity

a
↑ ATP hydrolysis

↑ Adenosine formation

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Via adenosine A1 receptors on macula densa cells

.
↑ Ca2+ release

K
Afferent arteriolar constriction

.
(vii) RBF, Renal VO and tubular reabsorption of sodium
2
(a) Renal VO correlates best with the rate of active reabsorption of Na+.
2
(b) There exists a linear relationship between renal VO and RBF (or GFR) above perfusion

A
2
pressure of 50 mmHg.

Notes:
1. RBF, GFR and filtered load of sodium determines renal metabolism.
2. An ↑ in ureteral pressure of one kidney reflexely leads to ↓ in efferent nerve activity to the contralateral
kidney to cause an ↑ in its exerction of Na+ and water, called Reno-renal reflex.

Mechanism of Formation of Urine

Filtration, secretion and reabsorption in kidney (Fig. 7.7)

Glomerular Filtration
1. Filtrate is ultrafiltrate wrt:
(i) osmolality, pH, electrical conductivity;
(ii) concentration of electrolytes, organic molecules;
(iii) practically contains no protein and no cells.
8

Artery

Afferent arteriole
Glomerular capillary

Efferent arteriole
1

Bowman's space
2

n
Peritubular capillary
3

i
4 Vein

a
Urine
Fig. 7.7 Filtration, secretion and reabsorption in kidney Amount

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Excreted (4) = Amount filtered (1) + Amount secreted (2) –
Amount reabsorbed (3)

.
2. Glomerular Filtration Rate (GFR)
Definition:

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Normal: 125 mL/min = 170-180 L/day.

.
Notes: Unique features of glo. memb.
1. Absolutely impermeable to molecules > 4 nm or MW above 70,000, so waste products (page 107) can easily
cross it.

A
2. 50 times more permeable than systemic capillaries (because of large pore size).
3. Being negatively charged, filtration of cations is more.

3. Mechanism: (Fig. 7.8)

Hydrostatic pressure
(45 mm Hg)

Colloidal osmotic
Endothelial cell pressure (25 mm Hg)

Basement
membrane
Glomerular
capillary lumen

Bowman's
capsule space

Podocytes Hydrostatic Colloidal Net effective

pressure osmotic filtration
(10 mm Hg) pressure pressure
(essentially (10 mm Hg)
zero)
Fig. 7.8 A diagrammatic representation of mechanism of glomerular filtration.
(Note: Length of the arrows denotes magnitude and direction of the force.)

GFR = Kf × EFP (10 mmHg)

(Kf : filtration coefficient of glomerular membrane = 12.5 mL/min/mmHg)
Therefore, GFR = 12.5 {(45 – 10) – (25 – 0)] = 12.5 × 10 = 125 mL/min.
  7: The Excretory System ❑ 9

4. Factors affecting GFR

Decreased by Increased by

(i) Old age due to ↓ cardiac output (i) ↑ in RBF (page 107)
(ii) MBP < 90 mmHg (ii) MBP > 220 mmHg

Note: Between 80-200 mmHg autoregulation →

normal GFR

(iii) Constriction of afferent arterioles (iii) Efferent arteriolar constriction

n
(iv) Dehydration → ↑ COPCap (iv) Hypoproteinemia → ↓ COPCap

i
(v) Mesangial cells contraction → ↓ size of (v) Mesangial cells relaxation → ↑ size of
capillary bed capillary bed
Causes

a
(a) angiotensin II Causes
(b) NE (a) ANP
(c) ADH (b) cAMP

J
(d) Endothelins (c) Dopamine
(e) histamine (d) PGE2

.
5. Glomerular versus Systemic Filtration
Glomerular Filtration Systemic Filtration

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(i) Capillary exchange area much less (320–480 cm2) (i) Enormous: 1000 m2

.
(ii) Filtration rate: 180 L/day (ii) 20L/day
6. Filtration fraction – GFR/RPF

A
Normal: 125 (mL/min) ÷ 700 (mL/min)
= 0.16 – 0.20, i.e., 16–20% of RPF.
(i) ↑ FF seen in: Hypotension → efferent arteriolar constriction → ↑ GFR and ↓ RPF.
(ii) ↓ FF seen in: Hypertension → efferent arteriolar relaxation → ↓ GFR and ↑ RPF.

Reabsorption and Secretion in Renal Tubules

General (Fig. 7.9)
PCT cell

Tubular Peritubular
lumen capillary

Reabsorption
Tight junction (Transcellular)
Lateral intercellular space

Reabsorption
(Paracellular)

Secretion
(Transcellular)

Apical membrane
(contains microvilli)

Basolateral Basal
membrane membrane
Fig. 7.9 Arrangement of PCT cells with major modalities of renal
transport (Note: Tight junction between cells in the PCT are leaky)
 10

1. Secretion
–
2. Reabsorption Note: Glucose, amino acids and HCO3 are 100% reabsorbed
3. Filtered load i.e., amount of solute transported across the glomerular membrane per unit time.
4. Excretion rate – amount of a substance that appears in urine per unit time.
(i) if excretion rate > filtered load → net tubular secretion of a substance; (creatinine is 100%
excreted)
(ii) if filtered load > excretion rate → net reabsorption of a substance.
5. Renal tubular transport maximum (Tm) – The maximal amount of a given solute that can be transported
(reabsorbed or secreted) per minute by the renal tubules.
6. The PCT reabsorbs: 70-85% of filtered Na+, Cl–, HCO3– and water; and almost 100% of filtered K+,
HPO42–, amino acids and glucose.

n
7. Glucose appears in urine when renal threshold is exceeded i.e., 200 mg glucose per 100 mL of arterial

i
plasma.
8. Reabsorption of water is passive and reabsorption of solutes can be passive or active.

a
Glucose Reabsorption
1. Rate of filtration of glucose: 100 mg/min (plasma glucose level × GFR =

J
80 mg/dL × 125 mL/min).

.
2. Glucose reabsorption & secretion is function of plasma glucose (PG). (Fig. 7.10)
(i) at low PG → 100% glucose reabsorption from PCT;
(ii) at PG > 180-200 mg/dL → glycosuria
(Renal threshold for glucose):

K
(a) ↑ed in old age and extreme DM;

.
(b) ↓ed in renal diabetes.
(iii) Tubular maximum for glucose (TmG):
(a) in men: 375 mg/min,

A
(b) in women: 300 mg/min.
(iv) When glucose is filtered @ 100 mg/min, PG is 80 mg/dL, thus if glucose is filtered @ 375 mg/ min,
PG will be: 80 × 375/100 = 300 mg/dL, called predicted renal threshold for glucose.
Filtered
load α PG Glucose filtered (mg/min)
600 PG (mg/dL)
(PG × GFR/100)
Glucose transport – TG

500
Ideal 80 100
TmG curve
400 100 125
Reabsorbed
(mg/min)

300 Actual 200 250

curve
200 Splay 300 375

100
400 500
500 625
0
0 200 400 600 800 1000 600 750
Plasma glucose conc. – PG (mg/dL)

Fig. 7.10 Relation between the plasma glucose concentration (PG) and glucose transport

(v) Actual renal threshold for glucose is: 200 mg/dL of arterial plasma or 180 mg/dL
of venous plasma, because not all the 2.6 million nephrons in the kidney have exactly the same
TmG → Splay in the curve relating PG to glucose transport.
3. Mechanism of glucose reabsorption: (Fig. 7.11)
(i) In the luminal border – passively via symport (glucose and Na+ bind to a common carrier);
(ii) Into the lateral intercellular spaces – actively (secondary to active transport of Na+);
(iii) Into the peritubular capillaries via GLUT-2 by facilitated diffusion.
  7: The Excretory System ❑ 11

Na+ (Lateral intercelluar space)

Tubular Na+-K+ Peritubular

lumen ATPase capillary

Na+ Na+
Glucose
Glucose (facilitated
Glucose
diffusion)

i n
Carrier GLUT-2
(symport i.e. SGLT-2)

a
Fig. 7.11 Glucose reabsorption from PCT
(SGLT-2: Sodium dependent glucose transporter-2
GLUT-2: Glucose transporter-2)

. J
Na+ Reabsorption
1. 98% of the filtered load of sodium is reabsorbed:
(i) 60% by PCT

K
(ii) 20% by loop of Henle
(iii) 15% by DCT

.
(iv) 2-3% by CT
(v) remaining 2% is excreted in urine.

A
A. Reabsorption from PCT: occurs in 2 steps. (Fig. 7.12)
  Step 1: Through apical (luminal) membrane passively down electrical and chemical gradient by
facilitated diffusion.
Na+ – K+
Tubular Na+ ATPase Peritubular
lumen capillary

Na+ Na+ PCT Basement

cell membrane
Glucose Symporter
Glucose Glucose
Cl–
–10 mV –70 mV +ve
140... 40... 140...

Tight
Na+
junction NaCl NaCl
H 2O

Na+ Na+

H+ Antiporter

Apical Basolateral
membrane membrane
Active transport
Passive transport

Fig. 7.12 Sodium reabsorption from PCT

(.. Na+ conc. mM/kg water)
12

  Step 2: Through basolateral membrane actively into lateral intercellular space; energy provided by
Na+ – K+ ATPase.
B. Reabsorption from DCT and CT
(a) 75% reabsorbed passively by chloride driven sodium transport.
(b) 25% by two electrically linked cation-exchange processes: Na+ – H+ and Na+ – K+ exchanger – these
processes involve Na+ reabsorption for H+ and K+ secretion respectively.
2. Factors affecting Na+ reabsorption

Increased by Decreased by
(i) ↓ CHP (i) ↑ CHP
(ii) ↑ COP (ii) ↓ COP

n
(iii) ↓ GFR (iii) ↑ GFR → Na+ excretion > Na+ reabsorption

i
(iv) ↓ ECFV (iv) ↑ ECFV
(v) Aldosterone (v) Glucocorticoids

a
(vi) ↓ Salt intake
CHP: Peritubular capillary hydrostatic pressure

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COP: Colloidal osmotic pressure

.
3. Regulation of Na+ excretion: Amount of Na+ reabsorption (from PCT) α GFR; Glomerulo tubular
balance. Mechanism:

↑ GFR

. K
↑ solute and water reabsorption from PCT

↑ fluid delivery to loop of Henle and 1st part of DCT

A
↑ solute reabsorption in thick ascending limb of loop of Henle

K+ Transport
1. Completely filtered at the glomerulus; only plasma electrolyte that is both reabsorbed and secreted
into renal tubules.
Tubular Na+ – K+ ATPase Peritubular
lumen capillary

K+

in intracellular
K+ Passive [K+]

Apical membrane Basolateral membrane

Fig. 7.13 Potassium transport in distal convoluted tubules

2. Reabsorption occurs actively in PCT (90% of the filtered load); ascending limb of Henle, DCT and CT.
(Fig. 7.13)
3. Secretion involves an active and a passive process; largely a function of PCT and is influenced by
aldosterone.
  7: The Excretory System ❑ 13

4. Factors affecting
Decrease Secretion Increase Secretion
(i) Depletion of S. K+ and (i) Excess of S. K+ and S. Na+
S. Na+
(ii) ↑ H+ secretion in DCT (ii) ↓ H+ secretion

Note: In DCT, K+ and H+ both compete for

Na+ reabsorption mechanism

(iii) ↓ rate of flow of fluid through DCT. (iii) ↑ rate of flow of fluid through DCT.
(iv) – (iv) Aldosterone → ↑ Na+ – K+ pump activity and

n
↑ permeability of DCT to K+.

i
HCO3– Reabsorption
Occurs throughout the nephron, except in the descending limb of loop of Henle.

a
A. Reabsorption from PCT (Fig. 7.14)
1. 90% by secondary active transport (antiport) via Na+–K+ exchanger.

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Tubular Peritubular

.
lumen capillary
PCT cell
Na+ Na+
Na+ – H+ Na+

K
Na+ – K+ ATPase
HCO3– H+ H+ exchanger
(Antiport) K+
F S

.
H+ HCO3– Na+
H+ pump H2CO3
Secondary
H2CO3
active
CA CA
transport

A
H 2O CO2 CO2 H 2O Cl.–
H 2O

F : filtered
S : secreted

Fig. 7.14 Bicarbonate reabsorption in proximal convoluted tubule (PCT)

(it accounts for largest fraction of HCO3– reabsorption)

2. Mechanism:
‘CA’
(i) In the lumen: HCO3– (F) + H+ (S) H2CO3 → CO2 + H2O

‘CA’
(ii) Within PCT: CO2 + H2O H2CO3 → H+ + HCO3– (newly synthesized). It is reabsorbed
actively into the blood along with Na+; and H+ is secreted again by H+ pump into the
lumen.

Note: The HCO3– reabsorbed into the blood is synthesized within the PCT and not the same HCO3– that was
filtered.

B. Reabsorption from DCT and CT (Fig. 7.15)

Occurs via a mechanism that involves the exchange of Na+ for K+ or H+ (as in the PCT).

Notes:
1. The renal contribution of new HCO3– is accompanied by the excretion of an equivalent amount of acid in the urine in
the form of titratable acid, NH4+ or both.
–
2. In hyperventilation (e.g. high altitude)→↑ CO2 washout→↓ H+ formation in renal tubular cells→↑ HCO3
excretion → alkaline urine.
14

Tubular Peritubular
lumen capillary

DCT cell
H+ Na+
H+ pump Na+ – K+ ATPase
K+
HCO3 – Cl.–
H+
H+ – K+ATPase
K+
H2CO3

CA
CO2 + H2O

i n
Fig. 7.15 Bicarbonate reabsorption in distal convoluted tubule

a
H+ Secretion
1. Occurs throughout the nephron except in descending limb of loop of Henle, permits conservation

J
of HCO3–.
2. (i) 85% occurs in PCT (very rich in ‘CA’).

.
(ii) 10% occurs in DCT.
(iii) 5% occurs in CT.
3. Mechanism: Occurs by active transport and is coupled to Na+ reabsorption, therefore, for each

K
mole of H+ secreted, one mole of Na+ and one mole of HCO3– are reabsorbed into the peritubular

.
capillaries.
4. Factors affecting: In general, conditions which increase the H+ secretion are associated with increase
HCO3– reabsorption. This is seen in:

A
(i) hypoventilation
(ii) hypokalemia
(iii) hypovolemia
(iv) decrease in plasma [Cl–]; and
(v) increased aldosterone secretion.

Cl– Transport (Fig. 7.16)

1. Cl– reabsorption 1/α HCO3– reabsorption.
2. Cl– is the chief anion to accompany Na+ through the renal tubular epithelium, therefore, plasma
[Cl–] is secondarily influenced by aldosterone.
Tubular Na+ – K+ Peritubular
lumen ATPase capillary

Na+
K+
K+
1Na+, 1k+
2Cl– Cl–
Cl–

Active transport or secondary active transport

Diffusion

Fig. 7.16 Chloride reabsorption in thick ascending segment of the

loop of Henle
  7: The Excretory System ❑ 15

Water Reabsorption
1. PCT: 60-70% of passive reabsorption of water occurs along the osmotic gradient set by the active
transport of solutes (e.g., glucose, Na+, HCO3– and Cl–).
2. Loop of Henle: 5-10%.

Note: Tubular fluid entering the descending limb of the loop of Henle is always isosmotic regardless of the
hydration state.

(i) Descending limb; highly permeable to water but the ascending limb is impermeable, → descending
limb becomes hypertonic.
(ii) In the ascending limb, it becomes hypotonic (because of the movement of Na+ and Cl– out of
the tubular lumen.

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3. DCT and CT

i
Note: Tubular fluid entering DCT is always hypotonic, regardless of the hydration state.

a
(i) Early part (relatively impermeable to water) continued removal of solutes in excess of solvent
→ further dilutes the tubular fluid. Approx. 5-8% of filtered water is removed passively.
(ii) Terminal part, 10-12% of filtered water is reabsorbed by ADH.

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Note: In the presence of maximal ADH effect, >99% of water is reabsorbed; in the absence of ADH, 88% of water

.
is reabsorbed → ↑ urine flow upto 20L/day (i.e., 15 mL/min; normal: 1 mL/min).

Important Points

K
1. Passive reabsorption of water in PCT secondary to active reabsorption of solutes is called obligatory

.
reabsorption of water.
2. Reabsorption of water in DCT and CT by ADH is facultative reabsorption of water (P i.e. principle
cells ↑s permeability of CT to water in the presence of ADH).

A
3. Urine volume cannot be <400 mL/day; called obligatory volume of urine.
4. Rapid transport of water depends on water channels made up of aquaporins; aquaporins 1 and 2
play a key role in water transport by their localization in PCT and CT respectively.
Summary: Process of Filtration, Reabsorption and Secretion in the Nephron
PCT
Reabsorption (into blood) of filtered:
(i) Water 65–75% (Osmosis)
(ii) Na+ 65% (Na+ – K+ pump, symporters, antiporters)
(iii) K+ 65% (Diffusion)
(iv) Glucose 100% (Symporters and facilitated diffusion)
(v) Amino acids 100% (Symporters and facilitated diffusion)
(vi) Cl– 65–75% (Diffusion)
(vii) HCO3– 80–90% (Facilitated diffusion)
(viii) Urea 50% (Diffusion)
Secretion
(i) H+ Variable (antiporters)
(ii) NH4+ Variable (antiporters)
(iii) Urea Variable (diffusion)
At the end of PCT, tubular fluid is ISOTONIC to plasma (300 mosm/L)
Loop of Henle
Reabsorption (into blood) of:
(i) Water 10–15% (osmosis in thin descending limb)
(ii) Na+ 20% (symporters in thick asending limb)
16

(iii) K+ 20–25% (symporters in thick asending limb)

(iv) Cl– 20–25% (symporters in thick asending limb)
(v) HCO3– 10–20% (facilitated diffusion)
Secretion
(i) Urea Variable
At the end of loop of Henle, tubular fluid is hypotonic to plasma (100–150 mosm/L)
Early part of DCT Late part of DCT
Reabsorption
(i) Water 5–8% (osmosis) 5–8% (under influence of ADH)
(ii) Na+ 15% (symporter) 2–3% (Na+ – K+ pump and Na+ channels stimulated by

n
aldosterone)

i
+
(iii) HCO –3 Variable Variable (to maintain acid-base homeostasis – H pump)
Secretion
(i) ­— K+ (Variable)

a
H+ (Variable)

J
Renal Clearance

.
General
1. Definition: The clearance value (Cx) of a substance
renal excretion rate of a substance (Ux V)

K
Cx = 
conc. of the substance in the arterial plasma (Px)

.
It is a measure of volume of plasma completely freed of a given substance per minute by the
kidneys.
2. Clearance value for urea (Curea  )

A
Amount of urea excreted in urine in
one minute
=
plasma concentration in urea
Uurea V
=
Purea

Normally,
Uurea : Urinary concentration of Urea
= 20 mg/mL.
V : Urine flow per minute = 1 mL/min.
Purea : Plasma concentration of Urea
(30 mg/dL). Therefore
20 × 100
Curea : = 67 mL/min.
30

Applications
A. As a measure of GFR
1. Principle.
2. Characteristic features of a suitable substance:
(i) Freely filtered.
(ii) Not reabsorbed or secreted by tubules.
(iii) Not metabolized to another substance.
(iv) Not stored in kidney.
(v) Not toxic and biologically inert.
  7: The Excretory System ❑ 17

(vi) Has no effect on filtration rate.

(vii) Preferably easy to measure in plasma and urine.
3. Clinically commonly used substances are:
(i) Inulin
(ii) Creatinine (Cr)
(iii) Mannitol
(iv) Sucrose
(v) Radioactive cobalt labelled Vit. B12
(vi) Radio iodine labelled hypaque
4. Inulin Clearance: Method (Fig. 7.17)
(i) A large initial dose of inulin is injected I.V., followed by constant infusion to compensate for

n
its loss in urine.

i
Afferent Glomerular
arteriole capillary
Renal artery

a
Pin = 1 mg/mL Efferent
arteriole

. J
Bowman's space

Amount filtered
= Amount excreted, i.e. zero% inulin

K
GFR × Pin = Uin × V reabsorbed
Uin × V

.
GFR =
Pin Peritubular
capillary
GFR = 125 mL/min

Renal vein

A
Urine
Uin = 125mg/mL (100% inulin
V = 1 mL/min excreted)

Fig. 7.17 Measurement of GFR from Inulin (in) clearance method

(Abbreviation as given in the text)

(ii) Inulin conc. in venous plasma (Pin), urinary concentration (Uin) and the urine volume excreted
per minute (V) are determined; then
Cin = UinV/Pin = 127 × 1/1
= 127 mL/min (normal)
(iii) Significance
(a) When Cx equal Cin (i.e. GFR), excretion is by filtration alone. Examples: mannitol, Vit. B12.
(b) When Cx < Cin, excretion is by filtration and reabsorption. Examples: glucose, xylose and
fructose.
(c) When Cx > Cin, excretion is by filtration and secretion. Examples: para-aminohippuric acid
(PAH), phenol red, creatinine.
5. Creatinine clearance
(i) Commonly used in clinical practice.
(ii) Does not require administration of exogenous creatinine.
(iii) Endogenous creatinine clearance is easy to measure.
(iv) Normal: 80–110 mL/min.
(v) Limitations: not for precise measurement of GFR
18

B. As a measure to estimate tubular secretory capacity: PAH clearance

1. PAH actively secreted into PCT by transport max. (Tm) process. (Fig. 7.18)
2. 10% of the plasma PAH is bound to plasma proteins, PAH is not entirely freely filtrable and
plasma PAH concentration (PPAH) is greater than that in the glomerular filtrate.
3. As the TmPAH is nearly constant, it is used clinically to estimate tubular secretory capacity (TS).
TmPAH is about 80 mg/min.
Excreted

150

PAH transport (mg/min)

Splay
Secreted

n
100

i
TmPAH
50
Filtered

a
0
0 20 40 60 80

J
PPAH (mg/dL)

Fig. 7.18 Relation between plasma PAH

.
concentration (PPAH) and PAH transport.

C. As a measure of Renal Plasma Flow (RPF) and Renal Blood Flow (RBF)

K
1. Principle: by applying Fick’s principle.

.
2. Criteria of the substance used: A substance
(i) completely extracted from the blood during each passage through the kidney;
(ii) neither metabolized, stored, nor produced by the kidney;

A
(iii) does not itself affect RBF;
(iv) its concentration in arterial and renal venous plasma can be measured easily; and
(v) is actively secreted by the tubules from the blood into their lumen.
3. Substances used are
(i) Diodrast (organic iodine compound).
(ii) PAH
4. RPF calculated from CPAH underestimate the actual flow by 10%. It measures the effective renal
plasma flow (ERPF),
i.e., ERPF = UPAH · V/APAH = CPAH (Normal: 700 mL/min)
5. RBF can be determined from ERPF as follows:
Total RBF = 100 × 700/55 (i.e., 100 – PCV).

D. As a measure of ‘osmotic’ and ‘free water’ clearance

1.Osmotic clearance (Cosm ) measures the rate at which plasma is cleared of osmotic particles.
Cosm = Uosm V/Posm
(V = rate of urine flow; Uosm and Posm urinary and plasma osmolality respectively)
Normally Cosm is 3 mL/min (↑ in osmotic diuresis, ↓ in fasting or protein deficient diet)
2.To quantitate the gain or loss of water by excretion of a concentrated or dilute urine, the ‘free
water clearance’ (CH O) is calculated:
2
CH O = V – Cosm
2

E. As a measure of excretion of waste products

1. Curea measure the rate of excretion of waste products.
  7: The Excretory System ❑ 19

2. Standard Urea clearance = U V/Purea, when rate of urine flow is < 2 mL/min
(Normal = 40–65 mL/min)
3. Maximal urea clearance, when rate of urine flow is > 2 mL/min (Normal : 60–90 mL/min)
Applied: Uremia
1. Definition: Accumulation of protein metabolism products (urea, creatinine, organic acid and phenol)
in the blood.
2. Cause: Chronic renal failure.
3. Signs and symptoms:
(i) Early: N, V, anorexia, anaemia, lethargy
(ii) Late: Impairment of higher mental function, muscle twitching, convulsions, coma and finally

n
death.

i
4. Treatment:
(i) Dialysis therapy i.e. process of separating soluble crystalloids from colloid in a mixture by means
of a dialyser (a semipermeable membrane of cellulose or cellophane, relatively impermeable to

a
protein and completely impermeable to blood cells). (Fig. 7.19 and 7.20)
Complications: anaemia; ↓ BP; hypopro-teinaemia, hypersensitivity reactions.

J
Cephalic
vein 1 Blood pump
Brachial Arterio-venous Dialysis fluid containing

.
Basilic artery anastomosis  Arterial blood from the filtrate of plasma
vein patient enters the dialyzer 2
Vein Artery Artery  The dialyzer
Dialyzer
removes waste
products from

K
blood by Movement of
Vein filtration dialysis fluid

.
Artery
Vein Strands of Fresh dialysis fluid
Graft
dialysis tubing
Movement
3 P
 urified blood is of blood

A
Arterio-venous
fistula returned to a vein
in the patient

(A) (B)

Fig. 7.19 Hemodialysis: (A) Arteriovenous fistula and (B) Technique

(ii) Kidney (or renal) transplant i.e. to place a healthy kidney from a live or dead donor into a
person whose kidneys are not functioning properly.
Indications: End stage renal disease (ESRD), it is associated with ↓ in GFR < 15 mL/min/1.73 m2
(Normal: 90–120 mL/min/1.73 m2BSA)
Failure rate: 3-4% - within 1 year
15-20% - within 5 years
20

Peritoneum

Solution
bag

Catheter

n
Connector

a i
J
Drainage bag

.
Peritoneal dialysis
solution

Fig. 7.20 Peritoneal dialysis

. K
Mechanism of Concentration and Dilution of Urine
(The Counter Current System)
General

A
1. Kidneys → urine formation which varies widely in its solute concentration
(i) in overhydration → urine of 50 mosm/L (i.e., 1/6th plasma tonicity); and
(ii) during dehydration → urine of 1200 mosm/L (i.e., 4 times plasma tonicity).
2. Counter current system (Fig. 7.21)
Definition:
Components:
(i) DLH;
(ii) Thin and thick segment ALH;
(iii) Medullary interstitium;
(iv) DCT;
(v) CT; and
(vi) Vasa recta.
Function: Concentrating and diluting system of kidney.

Mechanism of Concentration and Dilution

Depends upon the existence of a gradient of increasing osmolality along the medullary pyramids. This
gradient is:
1. produced by operation of the loop of Henle and CT as counter current multipliers; and
2. maintained by vasa recta as counter current exchangers.

A. Counter Current Multipliers (Fig. 7.22)

1. In PCT: fluid is isotonic to plasma (i.e., 300 mosm/L) as 75% of filtered solutes and water get
reabsorbed.
  7: The Excretory System ❑ 21

(A) (B)

Inflow = Outflow
15°C (at a constant
rate 10 mL/min)
15° 20°C

20° 25°C

25° 30°C

30° 35°C

35° 40°C

40° 45°C

50°C

n
45°C

i
20°C

a
Heat source
100 cal/min

. J
K
20°C

.
Fig. 7.21 The operation of a thermal counter current exchange
system (A) Heater surrounds a pipe and raises the temperature
of water flowing through the pipe by 5°C. (B) Pipe is bent into a

A
tight U-shape. The same heater applied at the base of the U sets
up a temperature difference throughout the length of the pipe, so
that at the bend the temperature is raised from 45 to 50°C.

urea
DCT NaCl
PCT
300 H 2O More
300 300 NaCl hypO
Cortex urea
400 H 2O
400 600 Outer Cl– Cl
400 200 400
ALH Medulla Na+ Na+ urea
600 (thick) Collecting
DLH 600 400 duct
600
Inner
hypO A DH
800 Medulla
800 inter- Urea
stitium H 2O H 2O
1000 H 2O
800 600 800 ADH
NaCl urea H 2O
hyper hypO
1000 1000 800 1200
ALH 1000 hyper NaCl hyper
(thin) To Ureter
1200 NaCl
1200 urea

(A) Vertical and Horizontal Osmotic difference (B) Solute and Solvent Transfer

Direction of tubular flow Active

(counter current) Passive

Water impermeability
Secondary active transport (symporter)

Fig. 7.22 Summary of changes in the Osmolality (in mosm/L) of tubular fluid in various parts of the Juxtamedullary nephron
ALH and DLH: Ascending and descending loop of Henle
22

2. Loop of Henle
(i) Descending limb: concentrating segment, as solute free water moves into the interstitium
because
(ii) Ascending limb: diluting segment, as Nacl diffuses out.
(iii) (i) and (ii) form a horizontal osmotic gradient of upto 200 mosm/L between ALH fluid and
the fluid of the interstitium.
3. DCT and CT
(i) Early DCT is relatively impermeable to water but CT is impermeable to urea and NaCl but
permeable to water. → ↑ medullary interstitium osmolality → +++ ↑ in urea conc. of tubular
fluid.
(ii) Inner medullary part of CT. ADH → urea along with water moves out passively into medullary

n
interstitium, → maintaining the high osmolality of the medullary pyramids → excretion of a

i
low volume, hypertonic urine.

B. Counter Current Exchangers: Vasa Recta (Fig. 7.23)

a
1. Medullary interstitium → traps the solutes Nacl & urea in the medullary interstitium and → ↑
medullary osmolality.
2. Water diffuses from the descending limb of vasa recta into the interstitium → ↑ conc. of plasma

J
proteins in the descending limb → ↑ oncotic pressure in the ascending limb of vasa recta → take
in the fluid.

.
Therefore, the solutes tend to recirculate in the medulla and water tends to bypass it → medullary
interstitium hyperosmolality is maintained.

K
Notes:

.
1. Medullary osmolality 1/α medullary blood flow;
2. Counter current exchange is a passive process.

A
Cortex

NaCl
Urea H 2O

Outer medulla

H 2O
H 2O
NaCl

Inner medulla Urea

H 2O

Fig. 7.23 The vasa recta function to maintain

the hyperosmolality of medullary interstitium
  7: The Excretory System ❑ 23

C. Role of Urea (Fig. 7.24)

1. (i) exert an osmotic effect on DLH;
(ii) promote the extraction of water;
(iii) ↑s intraluminal conc. of NaCl.
2. Creating a hyperosmolar state in the medullary interstitium.
3. The amount of urea in the final urine varies with the amount of urea filtered,
high protein diet → ↑ filtered load of urea → ↑s ability of kidney to concentrate the urine.
Collecting
duct

n
Cortex
Urea

i
NaCl Interstitium concentration
of NaCl is high here due to
NaCl its reabsorption in the thick
H 2O

a
ascending limbs of Henle
Outer medulla
Inner medulla Tubular urea concentration

J
Urea Urea is high here due to water
reabsorption above. Therefore,
urea diffuses into interstitium

.
H 2O increasing osmotic gradient for
additional water reabsorption.

Fig. 7.24 The differences between the relative NaCl and urea concentrations in tubular

K
fluid and the interstitium are represented by ‘Type size’

.
D. Other Examples of Counter Current System

Diuresis: Water versus Osmotic

A
Water diuresis Osmotic diuresis
1. Produced by drinking ≥ 1L of water or hypotonic 1. Presence of large quantities of unabsorbed
fluid, begins 15 minutes after ingestion of water solutes (such as Na+, glucose, urea) in the renal
load and reaches its maximum in 40 mins. tubules.
2. diuresis of dilute urine (50 mosmol/L) upto a 2. isotonic urine in spite of maximal ADH secretion
volume of 20L/day. and very large urine flow rates (>20L/day)
3. Mechanism: Water ingestion → ↓ ADH secretion. 3. ↓ water reabsorption in the PCT and loop of
Henle

Diuretics Agent Mode of Action Remarks

1. Water; Ethanol (–) ADH secretion Produces water diuresis
2. Glucose; mannitol Secretion of osmotically active Produces osmotic diuresis
subs. within renal tubules
3. Acetazolamide (Diamox) (–) CA →↓ H+ secretion (i) ↑Na+ & H+ excretion
(ii) ↓HCO3– reabsorption
(iii) Extensively used clinically
(iv) Hypokalemia (major SE)
4. Furosemide (Lasix) (–) Na+ – K+ – 2Cl– in thick ALH (i) Loop diuretic
SE (ii) (iii) & (iv) as above
5. Thiazidea (–) Na+ – Cl– co transport in DCT (iii) & (iv) above
SE
6. Spironolactone (–) Na+ – K+ exchange in CT (i) Commonly used clinically
(ii) Do not produce
hypokalemia
24

Acidification of Urine
General
1. Sources of H+
(i) CO2 as an end product of metabolism.
(ii) High protein diet.
(iii) Renal tubular generation of H+.
(iv) Non-carbonic acids: H2SO4, HCl, H3PO4 (phosphoric acid); ketoacids (acetoacetic acid, β‑hydroxy
butyric acid) and lactic acid.
2. Regulation of [H+] within normal limits:
(i) Combination of H+ with:

n
(a) blood buffer (HCO3–, haemoglobin)
(b) I/C buffer (organic or inorganic phosphate).

i
(ii) elimination of CO2 via respiration.
(iii) Renal elimination of H+.

a
Renal Regulation of Acid-Base Balance

J
A. Role of the Kidneys
–
1. HCO3 reabsorption by PCT and controlled reabsorption by DCT and CT of the filtered

.
HCO3–.
2. Excrete metabolically produced non-carbonic acid as H+, → normal urine acidic reaction.
3. The major sites of urine acidification are DCT and CT. All H+ within the tubular lumen is from the

K
tubular secretion of H+ generated by metabolism.

.
4. The kidney can cause a 1000 fold [H+] gradient between the plasma and urine. Because the
lowest pH attainable in urine is 4.4, called the limiting pH of urine.

A
Note: The buffers in the kidney operate so that this pH would not be reached rapidly, thus permitting more
acid to be secreted.

B. Buffer Systems in the Kidney

Major ones are: Bicarbonate, Dibasic phosphate and Ammonia system.
1. Bicarbonate system: Reaction with HCO3– . Since most of the secreted H+ is removed from the PCT,
the pH of the tubular fluid is changed very little; (it does not contribute to the urinary excretion of
acid).
2. Dibasic phosphate system: Reaction with Dibasic phosphate ions (HPO42–): (Fig. 7.25) The exchange of H+
for Na+ converts dibasic sodium phosphate (Na2HPO42–) in the glomerular filtrate into acidic sodium
dihydrogen phosphate (NaH2PO4–) and is excreted in the urine as titratable acid.
Na2HPO42– + H+ ⎯→ Na+H2PO4– + Na+
(filtered) (secreted)
  7: The Excretory System ❑ 25

Tubular Peritubular
lumen capillary
Tubular cell
Na+ Na+
Na+
HPO42– H+ H+ Na+–K+ ATPase
K+
F S Na+
Na+ HCO3–
HCO3–
Na+H2PO4– H2CO3
CA
CO2 + H2O

n
CA : Carbonic anhydrase

i
: Protein carrier
F : Filtered
S : Secreted

a
HPO42– : dibasic phosphate ion
H2PO4– : Monobasic phosphate ion

J
Fig. 7.25 Dibasic phosphate buffer system (The HCO3– that is
generated in the tubular cells and enters the peritubular capillary

.
blood represents a net gain of HCO3– by the blood, rather than
merely a replacement of filtered HCO3– (compare with Fig 54.10
on page 505).)

K
3. Ammonia system: Reaction with Ammonia (NH3) (Fig. 7.26)
(i) NH3 enters the tubular lumen by tubular synthesis and secretion, it is confined to the DCT and

.
CT.
(ii) NH3 (being lipid soluble) diffuses out of tubular cells along its concentration gradient, where
it combines with H+ to form ammonium ion (NH4+). NH4+ being lipid insoluble, stays in the

A
lumen.
Tubular Peritubular
lumen capillary
Tubular cell

Na+
Na+
A– H+ H+ Na+–K+ ATPase
K+
Na+
Na+ HCO3–
A–NH4+ HCO3–
NH3 NH3
H2CO3
CA
CO2 + H2O

Fig. 7.26 Ammonia buffer system (A– : Anion)

(iii) Ammonia system has a very high pK (about 9), therefore, at the usual urine pH of 6.0,
practically all of the NH3 that enters the DCT lumen immediately combines with H+ to form
NH4+. Ammonium excretion increases in linearity as the urinary pH falls below 6.0.
(iv) Amount of NH4+ formed α H+ secretion; thus, NH4+ content of an alkaline urine (pH > 6.0) is
nil, whereas that of maximally acid urine is high.

C. Titratable Acidity
1. The renal contribution of new synthesized HCO3– is accompanied by the excretion of an
equivalent amount of acid in the urine in the form of titratable acid, NH4+ or both. Therefore,
each H+ that reacts with buffer organic anions other than HCO 3– contributes to the urinary
titratable acidity.
26

2. Measured by determining the amount of alkali that must be added to the urine to return its pH
to 7.4 (i.e., normal pH of glomerular filtrate).
3. Attributed to the conversion of dibasic phosphate ions (HPO42–) to acidic phosphate ions
(H2PO42–).
4. It only measures a fraction of the acid secreted.
5. PCT is the major nephron site where it is formed.

Regulation of Volume and Concentration

of Body Fluids
General

n
1. Composition of body fluids is maintained by homeostatic mechanisms.

i
2. These mechanisms operate to maintain tonicity, the volume and the specific ionic composition
(particularly H+ concentration of ECF).

a
I. Defence of Tonicity (Fig. 7.27)
1. Normal plasma osmolality: 280-295 mosm/L.

J
If osmotic pressure of plasma s more than normal

.
Thirst controlling (i.e. osmolality of ECF s)
pathway
Thirst
(+) (+)

K
Osmoreceptors ADH secretion
(located in the anterior (from posterior pituitary)

.
Osmoreceptor Peripheral
cells volume receptors hypothalamus)

Hypothalamus (+)

A
Posterior
Thirst Inhibition
ADH pituitary

Water intake Water retention

Release of ADH
into capillaries
Dilution of ECF

Fig. 7.27 Mechanisms defending ECF tonicity; (+): Stimulation (Inset: Thirst controlling pathway)

2. It is primarily governed by:

(i) ADH (vasopressin); and
(ii) thirst mechanism.
3. Factors determining tonicity
Total body Na+ + total body K+
Total body osmolality =
Total body water (TBW)
4. Mechanisms defending tonicity:
↑ ECF osmolality →
(i) (+) osmoreceptor in anterior hypothalamus → (+) thirst → ↑ water intake
(ii) (+) ADH secretion → water retention.
(i) and (ii) → dilution of ECF → normal osmolality.

Note: The intensity of thirst and ADH secretion α the plasma osmolality.

5. Significant changes in ADH secretion occurs when plasma osmolality is changed as little as 1%.
  7: The Excretory System ❑ 27

II. Defence of Volume

ECFV is determined by: plasma osmolality (mainly) and control of water excretion.

A. Plasma osmolality
Since plasma (Na+) accounts for 95% of the effective osmotic pressure, therefore, the amount of Na+ in
ECF is the most important determinant of ECFV. Mechanisms that control Na+ balance.

B. Control of Water Excretion Mechanisms

1. Role of ADH:
(i) 1-2% ↑ in plasma osmolality → (+) osmoreceptors (in anterior hypothalamus), and
(ii) 10% ↓ in effective circulating blood volume → (+) baroreceptors (venous and arterial).

n
(i) and (ii) → ↑ ADH secretion → ↑ permeability of DCT and CT to water → ↑ solute free water

i
reabsorption → ↓ water excretion.

Note: In general, plasma [Na+] is the primary determinant of ADH secretion.

a
2. Role of Angiotensin II (Fig. 7.28)
Haemorrhage, salt depletion, acute hypotension → ↓ ECFV → ↑ Renin secretion from JGA via renin-

J
angiotensin system → ↑ Angiotensin II formation →

.
(i) Generalised VC.
(ii) (+) secretion and synthesis of aldosterone → ↑ Na+ reabsorption in DCT and CT.
(iii) Stimulate ADH secretion → ↑ solute-free water reabsorption.
(iv) Stimulate thirst mechanism → ↑ water intake.

. K
Arteriolar
constriction
Kidney 1 BP

A
Lung
Liver Adernal
cortex
2 Aldosterone

3 Restore
(ACE) GFR
Angiotensinogen Angiotensin-I Angiotensin-II
Efferent arteriolar
constriction

[DCT] ECFV
+
4 Na
+
K
Cl
Active transport H2 O
Renal perfusion
Passive transport 5 Sympathetic activity
(via JGA)
[CT]

6 ADH H2 O
Renin
Posterior
pituitary

INHIBITION

Fig. 7.28 Renin-angiotensin-aldosterone system (ACE: Angiotensin converting enzyme)

(ii), (iii) and (iv) → increase ECFV.

Important Note: By restricting the renal excretion of Na+, aldosterone regulates the ECFV. i.e. total body Na+
content; while ADH regulates the plasma Na+ concentration by conserving total body water.
28

3. Role of atrial natriuretic peptide (ANP)

(i) ANP (a polypeptide) produced by atrial muscle cells due to ↑ Nacl intake and/or ↑ in ECFV.
(ii) It inhibits renin secretion →↓ angiotensin II → Natriuresis and diuresis.

III. Defence of H+ Concentration

1. The intra and extracellular pH are maintained at very constant level of 7.1 and 7.4 ± 0.05
respectively by buffers in the body fluids.
2. The principal buffers in the body fluids i.e., ‘body buffer systems’
(i) Whole blood
(a) Haemoglobin system
(H Hb H+ + Hb–)

n
• Six times the buffering capacity of the plasma proteins.

i
• Reduced haemoglobin (Hb–) dissociate less making it a more effective buffer.
(b) Protein system (H Prot H+ + Prot–)
(c) Carbonic acid-bicarbonate system (H2CO3 H+ + HCO3–).

a
Note: H2CO3 level in plasma is in equilibrium with the dissolved CO2 which is controlled by respiration and
–
plasma [HCO3 ] is regulated by kidneys.

J
(ii) Interstitial Fluid – carbonic acid-bicarbonate system

.
(iii) Intracellular Fluid
(a) Protein system effective buffers, because both their free carboxyl (COOH) and their free
amino (NH3+) groups dissociate.

K
(b) Phosphate system
(H2PO4– H+ + HPO42–).

.
It is important intracellularly and plays a significant role in the urine.

Acid-Base Abnormalities (Table 7.1).

A
Table 7.1: Disturbances of acid-base balance and their compensation

Arterial plasma
Compensatory
Condition Definition HCO3– pCO2 Causes
pH mechanism
(mEq/L) (mmHg)
Normal – 7.40 24 40 – –
1. R
 espiratory ↓ arterial 7.34 25 48 • ↓ in alveolar Renal tubules →
Acidosis pH (↑[H+]), ventilation (i) ↑ H+ secretion and
↑ pCO2 and • Emphysema excretion in urine.
↑ plasma (ii) ↑ HCO3–
[HCO3–]. reabsorption →.
↑ arterial pH.
2. R
 espiratory ↑ arterial pH 7.53 22 27 • hyperventilation Renal tubules →
Alkalosis (↓[H+]), • Anxiety (i) ↓ H+ secretion &
↓ pCO2, and H+ retention
↓ in plasma (ii) ↓ HCO3–
[HCO3–] reabsorption →
↓ arterial pH.
3. M
 etabolic ↓ arterial 7.28 18 40 • Accumulation of (i) ↑ plasma [H+] →
Acidosis pH (↑[H+]), ketoacids (DM) or (+) respiration → ↓
or ↓ plasma LA (Ex). art. pCO2 → ↑ pH
[HCO3–]. • Loss of HCO3– : (ii) ↑ renal tubular
severe diarrhoea, excretion of H+
→ ↑ HCO3–
reabsorption.
  7: The Excretory System ❑ 29

4. M
 etabolic ↑ arterial 7.50 30 40 ↓ production or loss (i) ↓ plasma [H+]
Alkalosis pH (↓[H+]) of acid via - kidneys →(–) respiration
or ↑ plasma or GIT (vomiting) → ↑ art. pCO2 →
[HCO3–] normal arterial pH.
(ii) ↑ HCO3– excretion
in urine
uncompensated state

↓ : decrease; ↑ : increase

n
Anion Gap
1. It is the difference between the concentration of cations (other than Na+) and the concentration of

i
anions (other than Cl– and HCO3–) in the plasma. (Fig. 7.29)

a
(A) (B) Increased anion gap: metabolic acidosis
Sodium Chloride
Bicarbonate
Lactic acidosis: Ketoacidosis:

J
LH L– + H+ βHBH βHB– + H+
AAH AA– + H+

.
Albumin
Phosphate
Normal UA– UA– UA– UA–
IgA
anion L– βHB–
gap HCO3– HCO3– AA–
HCO3–

K
Na+ Na+ Na+ Na+ HCO3–

.
Potassium Cl– Cl– Cl– Cl–
Calcium
Magnesium
IgG Increased Unmeasured Anions (UA–) Increased Unmeasured Anions

A
Fig. 7.29 Anion gap (A) Normal and (B) in disease conditions (LH: Lactic acid; βHBH: βhydrooxybutyric acid–ketoacid)

2. It includes proteins in the anionic form (dibasic phosphate ions; HPO42–; sulphate ions: SO42–) and
organic acids.
3. Normal value: 12 mEq/L. How? [Na+] – [HCO3–] – [Cl–] i.e. 145 – 24 – 109 = 12 mEq/L.
4. Advantage: helps clinically in diagnosing acid base status, specially of metabolic acidosis.
5. Factors affecting

Increase in Decrease in
(i) ↓ in plasma concentration of K +,
or Ca2+ Mg2+ (i) ↑ in cations.
(ii) ↑ in concentration of unmeasured anions essentially plasma proteins (ii) ↓ in plasma albumin
(iii) Metabolic acidosis

Physiology of Micturition
Definition
Urinary bladder: Physiological anatomy
1. The body comprises detrusor muscle.
2. Internal sphincter in the trigone. Functions:
3. External sphincter – voluntary skeletal muscle.
30

4. Physiological capacity
(i) At birth : 20-50 mL
(ii) At 1 year : 200 mL
(iii) Adults : 600 mL
5. Anatomical capacity: 1L (capacity just before bladder ruptures)
6. Nerve supply (Fig. 7.30)
(i) Afferent
(a) From external sphincter and posterior urethra along the pudendal nerve into S2,3,4.
(b) From body, trigone and internal sphincter take double route:
• along sympathetic nerve into L1,2;
• along parasympathetic nerve into S2,3,4.

n
Lateral sympathetic chain

i
Spinal cord
Coeliac ganglion L1

a
L2
Superior mesenteric ganglion
Efferent sympathetic

J
nerve
Pre-ganglionic

.
neuron
Pre-sacral nerve

Hypogastric nerves

K
Efferent parasympathetic

.
nerve Hypogastric
ganglia
Afferent
S2 nerves

A
S3
S4 Pelvic nerve
(nervi erigentes)
Anterior primary
Body
divisions
Efferent
somatic S2
nerve S3
Trigone
S4

Internal sphincter Pudendal nerve

Posterior urethra
Afferent somatic
External sphincter nerve

Fig. 7.30 Innervation of the urinary bladder

Functions
(a) Indicate degree of distension of UB;
(b) Convey pain.
(ii)
Efferent
(a) Sympathetic (L1,2 segment) via presacral nerve → hypogastric nerve → body and internal
sphincter → retention of urine
(b) Parasympathetic (S2,3,4) via pelvic nerves (nervi erigentes) → hypogastric ganglia → body
and internal sphincter → emptying of bladder.
(c) Somatic (S2,3,4) via pudendal nerve → posterior urethra and external sphincter → under
higher control → reflexly and voluntarily relaxed at the time of micturition.
  7: The Excretory System ❑ 31

Postural Activity of the Urinary Bladder

1. Normal urinary bladder muscle shows property of plasticity
2. Cystometrogram: (Fig. 7.31)
(i) Components:
(a) Segment Ia
(b) Segment Ib
(c) Segment II: → (+) micturition reflex
Intra-vesical pressure (cm H2O) 100

80
ves
wa II

n
)
ct ion
60 a
ntr

i
If no
(co micturition
n
ri tio had
40 ctu
Mi occurred

a
20 Ib
Ia

J
0
0 100 200 300 400 500

.
Intra-vesical volume (mL)

Fig. 7.31 Cystometrogram in normal human

(iii) Superimposed on cytometrogram are micturition (contraction) waves which last few seconds to

K
a minute. These are result of stretch reflex initiated by stretch receptors in the bladder. Stretch

.
receptors have a low threshold.

Mechanism of Voluntary Micturition and Its Reflex Control (Fig. 7.32)

A
1. Afferent pathway: → Desire to micturate.
2. Efferent pathways: → emptying of bladder.
3. Higher control of micturition reflex
(i) Facilitatory areas: pons and posterior hypothalamus.
(ii) Inhibitory area: mid-brain.

Note: Basically, micturition reflex is a spinal reflex facilitated and inhibited by higher brain centres.

4. Accessory muscle involved during micturition

(i) perineal muscles
are relaxed; → ↑ intra-abdominal
(ii) abdominal wall pressure →
↑ intra-vesicle
muscles contract;
pressure → bladder
(iii) diaphragm descends; emptying
(iv) breathing is held with
glottis closed.
5. After urination, female urethra empties by gravity while male urethra by contraction of bulbo-
cavernosus muscle.
32

Pons
(+)
2

Thoracic/lumbar spinal cord

1 A
 fferent impulses from stretch
receptors to pons
(–)

n
2 P
 ontine micturition center
I
4 activated

i
n
t
e 3 P
 arasympathetic efferents
r stimulate detrusor muscle,

a
n opening internal urethral
Inferior hypogastric ganglion e sphincter
u
r
o 4 S
 ympathetic efferents

J
Hypogastric nerve n inhibited
Pelvic nerves

.
5 S
 omatic efferents inhibited;
1 external urethral sphincter
Urinary bladder relaxes
Stretch receptors (+)
(–)

K
3

.
Sacral
Pelvic splanchnic
spinal
nerves
cord

A
Internal urethral sphincter 5
External urethral sphincter

Urethra

Fig. 7.32 Neural pathway for micturition reflex. (Sequence of events 1 to 5 ) (+): Excitation, (–): Inhibition

6. First urge to pass urine is felt at: 150 mL bladder volume.

7. Marked sense of fullness: 400 mL
8. Desire to hold urine
9. By constant practice bladder can be trained to accommodate very large volume of urine.
10. Even moderate filling upto 200 mL, desire to micturate → sharp ↑ in intravesicle pressure →
micturition.
11. In young children, postural activity of bladder is less perfect and even small volume of urine → (+)
micturition reflex (higher centres not involved).
12. Postural activity can be influenced by: emotional stress or inflammation or bladder stone, → constant
desire to micturate with passage of small quantities of urine each time.

Applied

Note: In all types of bladder dysfunction → residual urine (Fig. 7.33)

1. Deafferentation
Automatic bladder → distended thin walled and hypotonic bladder.
  7: The Excretory System ❑ 33

Thickened
urinary bladder
wall

Residual
urine

Enlarged
prostate

i n
Urethra

a
Fig. 7.33 Residual urine

2. Denervation

J
Isolated or decentralized bladder;
3. Transection of Spinal Cord

.
(i) Early Stage
Voluntary control is completely lost; UB: flaccid, distended and unresponsive; followed by
→ retention of urine → overstretching of bladder wall → retention with overflow (or overflow

K
incontinence);
(ii) Late Stage

.
(a) No voluntary control, can be initiated by activating mass reflex;
(b) Repeated infection of UB → spastic (or contracted) neurogenic bladder. (Fig. 7.34)
Urinary bladder

A Sphincter
muscles
Urine

Urethra,
closed

Sphincter
Urethra,
open

squeezed shut muscles

relaxed

Fig. 7.34 Spastic neurogenic bladder

Regulation of Body Temperature

General
1. Poikilothermic animals: Cold blooded (reptiles, fish)
2. Humans are homeothermic and can maintain constant body temperature within a narrow range in
spite of wide variations in environmental temperature.
3. Neural (or comfortable) zone temperature
4. Oral Temperature: 37°C (98.6°F); Range 36.3-37.1°C (97.3-98.8°F) (the temperature of the scrotum is
carefully regulated at 32°C).
34

5. Core (or Internal body) Temperature (Fig. 7.35)

(i) 0.5-1°C more than oral temperature.
(ii) Hypothalamic thermoregulatory receptors are exposed to it.
(iii) Varies least with environmental temperature.
(iv) Sites:
(v) Upper lethal value: 43.5°C → (death due to heat stroke).
(vi) Lower lethal value: 26°C → (death due to cardiac failure).
(vii) > 41°C → irreversible brain damage.
43.5ºC Upper lethal

n
Sweating

i
Core body temperature
Vasodilation

37ºC

a
Normal body temperature
36ºC

Vasoconstriction

J
Shivering

.
26ºC Lower lethal

K
Fig. 7.35 Core temperature

.
Factors Affecting Body Temperature
1. Age

A
(i) Infants: more by 0.5°C due to
(ii) Old age: subnormal because:
2. Sex: in females, slightly low due to:
3. Constitutional hyperthermia.
4. Diurnal variations upto 1.5°C
5. Diseases
(i) hyperthyroidism
(ii) hypothyroidism (myxoedema)
6. Exercise ↑s upto 40–41°C
7. Emotional factors: ↑ temperature by 2°C.

Body Heat Production and Heat Loss

A. Heat Production – Thermogenesis (Fig. 7.36)
  7: The Excretory System ❑ 35

Factors Increasing

Heat loss
Heat Production
(Thermogenesis)
1. To the surroundings by
Radiation; Conduction;
1. Metebolic activities of the Convection
body in:
Skeletal muscle, liver, heart
2. By Water Evaporation
2. Specific Dynamic action of
Sweating; Insensible water
food

n
loss; Respiration
3. Heat gained from

i
the surrounding hot
environment by: 3. By Excretion
Direct and Reflected radiation Urine; faeces

a
4. Endocrine mechanisms
Ep, NE, T4
5. Brown fat 4. Cutaneous Vasodilatation

J
(specially in infants)
6. Exercise; increased 5. Decreased clothing

.
voluntary activity
7. Shivering
8. Increased food intake 6. Increased air movements

. K
A
35°C 39°C
(Fever)

37°C (Normal)

Fig. 7.36 Balance between factors increasing heat production and heat loss

Note:
1. Vaporization of 1 g (1 mL) of water removes about 0.6 kcal of heat.
2. Average water loss:
  (i) from lungs: 300 mL/day = 200 kcal.
(ii) through skin: 50 mL/hour = 30 kcal/hour (it can be as high as 1.6L/hour = 900 kcal/hour.

Temperature Regulating Mechanisms (Fig. 7.37)

1. Thermoregulatory Responses Activated by Exposure to Cold (via posterior hypothalamus)
(i) ↑ Heat Production: (i) Shivering; (ii) Hunger; (iii) ↑ voluntary activity; (iv) ↑ TSH secretion and (v)
↑ catecholamine secretion.
36

Sweat glands secrete sweat that

Thermoregulation evaporates, Cooling the body
center in ‘anterior
hypothalamus’ is
activated

Blood vessels in
skin dilate and
heat escapes
Temperature rises
above normal

i n
Homeostasis:
Internal body temperature
of 36.5–37.5ºC

a
Temperature fails

J
Blood vessels in below normal
skin constrict,

.
minimizing heat loss

. K
Skeletal muscles rapidly Thermoregulation
contract, causing shivering center in ‘posterior
which generates heat hypothalamus’ is
activated

A
Fig. 7.37 Temperature regulation mechanisms

(ii) ↓ Heat Loss: (i) Cutaneous VC; (ii) Curling up and (iii) Horripilation → Goose pimples.

2. Thermoregulatory Responses Activated by Exposure to Heat (via anterior hypothalamus)

(i) ↑ Heat loss: (i) Cutaneous vasodilation; (ii) Sweating and (iii) ↑ pulmonary ventilation.
(ii) ↓ Heat production: (i) Anorexia; (ii) Apathy → ↓ body activity and (iii) ↓ TSH secretion.

Control of Heat Production and

Heat Loss
A. Role of Nervous System
1. Afferents come from: (i) Temperature sensitive cells in anterior hypothalamus, (ii) Cutaneous temperature
receptors, specially cold receptors, get activated by exposure to cold.
2. Efferents projected to somatic and ANS ventilation.
  7: The Excretory System ❑ 37

Notes:
1. In general, skin receptors respond to rapid environmental temperature changes, and hypothalamic receptors
compensate for changes in endogenous heat production and prevent overcompensation by skin reflexes.
2. The anterior hypothalamus: centre for responses to rising temperature and the posterior hypothalamus: centre for
responses to falling temperature.
3. 5-HT is a synaptic mediator in the centres controlling the mechanisms activated by cold; NE plays a similar
role in those activated by heat.

B. Role of Endocrines

n
1. Adrenal medulla: Its effect is rapid and of short duration.
2. Thyroid: Its effect is slowly developing but prolonged.

i
3. Adrenal cortex

a
Applied
1. Fever
(i) Fever → thermostat reset to a new point above 37°C → activation of temperature raising

J
mechanisms.

.
(ii) Pathogenesis
Bacterial endotoxin; inflammation; pyrogenic stimuli → (+) Macropahges, Monocytes and Kupffer
cells → Cytokines and IL-1 (endogenous pyrogens) → (a) (+) preoptic area of hypothalamus →
↑ prostaglandins → fever;

K
(b) (+) immune system; (c) (+) bone marrow → ↑ neutrophil release and (d) proteolysis in the

.
muscle.
(iii) Benefits of fever
2. Hypothermia: Lower lethal core temperature 26°C → cardiac failure.

A
Use: Extensively in surgery.