9. • What is the osmolarity of a
5 % glucose solution ?
• Is the solution hyperosmotic,
hypo-osmotic, or isosmotic ?
Question
10. Osmolarity of a 5 % Glucose solution
MW glucose = 180 gm/mol
5 % = 5 gm/100 ml = 50 gm/L
Isosmotic
50 gm x 1 mol = .278 mol =
L 180 gm L
278 mOsm
L
11. Isosmotic - has same osmolarity as body fluids
Hyperosmotic - higher osmolarity than body fluids
Hyposmotic- lower osmolarity than body fluids
12. 40
300
200
100
0
0 10 20 30
OSMOLARITY
mOsm/L
Normal State
VOLUME (L)
ECF
ICF
1.
2.
3.
Effect of adding 2 L of 0.9 % NaCl ?
13. 40
300
200
100
0
0 10 20 30
OSMOLARITY
mOsm/L
Normal State
VOLUME (L)
ECF
ICF
1.
2.
3.
Effect of adding 2 L of 0.9 % NaCl ?
14. 40
300
200
100
0
0 10 20 30
OSMOLARITY
mOsm/L
Normal State
VOLUME (L)
ECF
ICF
1.
2.
3.
Effect of adding 2 L of 5 % Glucose (isosmotic)?
15. 40
300
200
100
0
0 10 20 30
OSMOLARITY
mOsm/L
Normal State
VOLUME (L)
ECF
ICF
1.
2.
3.
Instantaneously
Effect of adding 2 L of 5 % Glucose (isosmotic)?
16. 40
300
200
100
0
0 10 20 30
OSMOLARITY
mOsm/L
Normal State
VOLUME (L)
ECF
ICF
1.
2.
3.
Effect of adding 2 L of 5 % Glucose (isosmotic)?
Instantaneously
After metabolism of glucose
17. 40
300
200
100
0
0 10 20 30
OSMOLARITY
mOsm/L
Normal State
VOLUME (L)
ECF
ICF
1.
2.
3.
Effect of adding 2 L of 3 % NaCl ?
18. 40
300
200
100
0
0 10 20 30
OSMOLARITY
mOsm/L
Normal State
VOLUME (L)
ECF
ICF
1.
2.
3.
Effect of adding 2 L of 3 % NaCl ?
19. What are the Changes in the
following variables after giving
2.0 liters of 3% NaCl i.v. ?
Extracellular Fluid Volume ?
Extracellular Fluid Osmolarity ?
Intracellular Fluid Volume ?
Intracellular Fluid Osmolarity ?
> 2.0 Liters
22. Learning Objectives:
At the end of this lecture, students should be able to describe
• Functions of Kidney
• ‘Physiologic’ freedom
• Components of Urinary/Excretory/Renal system
• External features & location of kidneys & applied
aspects.
• Inner structure of kidneys
26. Regulation of Water and Electrolyte
Balances.
Excretion of water and electrolytes must
precisely match intake
27.
28. Balance Concept
Fluid and electrolyte balances are necessary,
in the long-term, to maintain life.
Fluid Loss = Fluid Intake
Electrolyte Loss = Electrolyte Intake
Fluid Intake: regulated by thirst mechanism, habits
Electrolyte intake: governed by dietary habits
Fluid Output: regulated mainly by kidneys
Electrolyte output: regulated mainly by kidneys
29. Effect of increasing sodium intake 10-fold
on urinary sodium excretion and
extracellular fluid volume
33. Regulation of Water and
Electrolyte Balances
• Sodium and Water
• Potassium
• Hydrogen Ions
• Calcium, Phosphate, Magnesium
34. Secretion, Metabolism, and
Excretion of Hormones
• Hormones produced in the kidney
• Erythropoietin
• 1,25 dihydroxycholecalciferol (Vitamin D)
• Renin
• Hormones metabolized and excreted by the kidney
• Most peptide hormones (e.g. insulin, angiotensin II,
etc.)
35. Regulation of Erythrocyte Production
O2 Delivery
Kidney
Erythropoetin
Erythrocyte Production
in Bone Marrow
36. Regulation of Arterial Pressure
Endocrine Organ
•renin-angiotensin system
Control of Extracellular Fluid Volume
37. Regulation of Vitamin D Activity
• Kidney produces active form of vitamin D
(1,25 dihydroxy vitamin D3)
• Vitamin D3 is important in calcium and
phosphate metabolism
38. Regulation of Acid-Base
Balance
• Excrete acids (kidneys are the only means of
excreting non-volatile acids)
• Regulate body fluid buffers (e.g. Bicarbonate)
40. Summary of Kidney Functions
• Excretion of metabolic waste products
urea, creatinine, bilirubin
• Excretion of foreign chemicals: drugs, toxins,
pesticides, food additives
• Secretion, metabolism, and excretion of hormones
- renal erythropoetic factor
- 1,25 dihydroxycholecalciferol (Vitamin D)
• Control of arterial pressure
• Regulation of water & electrolyte excretion
• Regulation of acid-base balance
• Gluconeogenesis: glucose synthesis from
amino acids
41. Physiologic Anatomy of the Kidneys
The earliest insights into renal
physiology came from the assiduous
study of anatomy because, to a large
degree, renal function follows
structure
43. Physiologic Anatomy of the
Kidneys
lie on the posterior wall of the
abdomen
outside the peritoneal cavity
Each kidney weighs about 150
grams
about the size of a clenched
fist.
44. Tenderness of Costovertebral angle
(pyelonephritis, renal stone, perinephric
abscess)
Because the kidney is directly anterior to this area, tapping disturbs the
inflamed tissue, causing pain.
46. Inner structure of kidney
A frontal section through kidney shows two
distinct regions:
1. Superficial (outer) renal cortex
2. Deep (inner region) is called renal medulla
Together, renal cortex & renal pyramids constitute renal parenchyma.
47.
48.
49. Functional Configuration of Kidney
Nephrons
↓
‘papillae of renal pyramids’
↓
Minor (8-9) and Major (3-4) calyces)
↓
Renal pelvis (pelv- basin)
↓
Out through ureter
↓
urinary bladder.
56. The renal circulation is unique
• It has two capillary beds, the glomerular and peritubular
capillaries, which are separated by the efferent arterioles, which
help regulate the hydrostatic pressure in both sets of capillaries.
• High hydrostatic pressure in the glomerular capillaries (about 60
mm Hg) causes rapid fluid filtration
• Lower hydrostatic pressure in the peritubular capillaries (about
20 mm Hg) permits rapid fluid reabsorption.
• By adjusting the resistance of the afferent and efferent
arterioles, the kidneys can regulate the hydrostatic pressure in
both the glomerular and the peritubular capillaries
59. The Nephron
• Functional Units of the kidney
• Approximately 1 million nephrons/ kidney.
After age 40 years, the number of functioning nephrons usually
decreases about 10 percent every 10 years.
• Total length of a nephron
(including collecting ducts) - 45 to
65 mm
60. Structure of Nephron
A nephron consists of :
I. Renal Corpuscles
(Spherical filtering
component)
II. Renal tubules
61. Bowman described glomeruli, 1842
Ludwig, 1842
Wearn and Richard,1924
Malpighi spotted glomeruli, 1666
Milestones in the discoveries of Structure and functions of Nephron
Micropuncture techniques
but mistakes how they work
gets it right
62. Micropuncture and “stop flow” techniques were used
to help define the role of each segment of the
nephron
72. Except for intercalated cells, all cells in the nephron have
in the apical plasma membrane a single nonmotile
primary cilium that protrudes into tubule fluid.
74. Urine Formation Results from
Glomerular Filtration,
Tubular Reabsorption, and
Tubular Secretion
75. Urine Formation
begins when a large amount of fluid that is virtually free of
protein is filtered from the glomerular capillaries into
Bowman’s capsule.
As filtered fluid leaves Bowman’s capsule and passes through
the tubules
it is modified by reabsorption of water and specific solutes back
into the blood or by secretion of other substances from the
peritubular capillaries into the tubules
77. Excretion =
Filtration - Reabsorption + Secretion
Filtration : somewhat variable, not selective (except for
proteins) , averages 20% of renal plasma flow
Reabsorption : highly variable and selective,
most electrolytes (e.g. Na+, K+, Cl-) and nutritional
substances (e.g. glucose) are almost completely
reabsorbed; most waste products (e.g. urea) poorly
reabsorbed
Secretion : highly variable; important for rapidly excreting some
waste products (e.g. H+), foreign substances
(including drugs), and toxins
78. • For each substance in the plasma, a particular
combination of filtration, reabsorption, and
secretion occurs.
79.
80. Rate at which the substance is
excreted in the urine depends on
the relative rates of three basic
renal processes (filtration,
reabsorption, and secretion).
81. Renal Handling of Various
Plasma Constituents in a Normal
Adult Human on an Average Diet
Substance Filtered Reabsorbed Secreted Excreted Percentage
Reabsorbed
Na+ (mEq) 26,000 25,850 150 99.4
K+ (mEq) 600 560 502 90 93.3
Cl– (mEq) 18,000 17,850 150 99.2
HCO3– (mEq) 4,900 4,900 0 100
Urea (mmol) 870 460 410 53
82. Substance Filtered Reabsorbed Secreted Excreted Percentage
Reabsorbed
Creatinine
(mmol)
12 1v 1v 12 0
Glucose
(mmol)
800 800 0 100
Total solute
(mOsm)
54,000 53,400 100 700 98.9
Water (mL) 180,000 178,500 1500 99.1
Renal Handling of Various Plasma
Constituents in a Normal Adult
Human on an Average Diet
84. Why Are Large Amounts of Solutes Filtered and Then
Reabsorbed by the Kidneys?
• Most waste products are poorly reabsorbed
Depend on a high GFR for effective removal from the body.
• High GFR allows all the body fluids to be filtered and processed by the
kidney many times each day.
• Plasma volume :- 3 liters
GFR :- 180 L/day
Entire plasma can be filtered and processed about 60 times each day.
Allows the kidneys to precisely and rapidly control the volume and
composition of the body fluids.
87. Glomerular Filtration(production of an ultrafiltrate of plasma across
the glomerulus)—The First Step in Urine Formation
• Urine formation begins with filtration of large amounts of fluid through
the glomerular capillaries into Bowman’s capsule (dilated, blind end of
the nephron).
• the filtered fluid (called the glomerular filtrate) is essentially protein-
free and devoid of cellular elements, including red blood cells.
• The concentrations of other constituents of the glomerular filtrate,
including most salts and organic molecules, are similar to the
concentrations in the plasma.
• Exceptions to this generalization include a few low-molecular-weight
substances, such as calcium and fatty acids, that are not freely filtered
because they are partially bound to the plasma proteins.
88. GLOMERULUS : FILTRATION UNIT
Substances Filtered
Substances Not Filtered
Water
Major elctrolytes :
Cations- Na+, K+,Ionized Ca++,Mg++
Anions- Cl-, HCO3-
Metabolic waste product :- Urea
,creatinine
Metabolites :- Glucose,Amino
acids,organic acids
Low molecular weight protiens – Insulin,
Hemoglobin
Inulin, PAH
Blood cells
Plasma Proteins
Note: calcium and fatty acids,
T3,T4 that are not freely filtered
because they are partially
bound to the plasma proteins
89. • Note that freely filtered does not mean all filtered.
• It just means that the amount filtered is in exact proportion to
the fraction of plasma volume that is filtered.
90. Glomerulus : Filtration unit of nephron
Glomerulus:-
tuft of capillaries Invaginated into the
dilated, blind end of the nephron (Bowman’s
capsule), embedded in mesangium
91. AFFERENT ARTERIOLE
(Divides into a tuft of
capillaries)
EFFERENT ARTERIOLE
Bowman’s capsule
GLOMERULAR BASEMENT
MEMBRANE AND
PODOCYTES
Bowman’s Space
Mesangial
cells
93. GLOMERULAR FILTRATION :- The
Glomerular Filtration Barrier Has
Three Layers
(1) the endothelium of the
capillary,
(2) a basement membrane,
and
(3) a layer of specialized
epithelial cells (podocytes)
of the capsule surrounding
the outer surface of the
capillary basement
membrane
94. GLOMERULAR FILTRATION :- The Glomerular Filtration Barrier Has Three
Layers But still high filtration rate ?
95. The high filtration rate across the
glomerular capillary membrane
• Endothelium of the
glomerular capillaries is
fenestrated
• Although the fenestrations are
relatively large, endothelial
cells are richly endowed
with fixed negative
charges that hinder the
passage of plasma proteins
96. The high filtration rate across the
glomerular capillary membrane
Basement
membrane:
consists of a meshwork of collagen
and proteoglycan fibrillae through
which large amounts of water and small
solutes can filter.
effectively prevents filtration of plasma
proteins, in part because of strong
negative electrical
charges associated with
the proteoglycans
97. The high filtration rate across the
glomerular capillary membrane
Podocyte :
• These cells are not continuous but have long
footlike processes (pedicels) that encircle the
outer surface of the capillaries.
• pedicels interdigitate to form
filtration slits wide along the capillary
wall.
• Extremely thin processes
called slit diaphragms bridge
the slits between the pedicels
• The epithelial cells, which also have
negative charges, provide additional
restriction to filtration of plasma proteins
98. Slit Diaphragm as rungs of ladder between
Foot processes of 2 adjacent podocytes
99.
100. Spaces between slit diaphragms
constitute the path through which
the filtrate, travels to enter
Bowman’s space.
101. Slit Diaphragm as rungs of ladder between
Foot processes of 2 adjacent podocytes
102. • while the basement membrane may
contribute to the selectivity of the filtration
barrier, integrity of the slit diaphragms is
essential to prevent excessive leak of plasma
protein (albumin). Some protein-wasting
diseases are associated with abnormal slit
diaphragm structure
103. • the effective pore size of the glomerular membrane (8 nm)
• Functionally, the glomerular membrane permits the free
passage of neutral substances up to 4 nm in diameter and
almost totally excludes those with diameters greater than
8 nm.
• However, the charges on molecules as well as their
diameters affect their passage into Bowman’s capsule.
• .
105. • albumin ~ 6 nanometers
pores ~ 8 nanometers
• Albumin is restricted from filtration, however, because of its negative
charge and the electrostatic repulsion exerted by negative charges of
the glomerular capillary wall proteoglycans.
• In certain kidney diseases, the negative charges on the basement
membrane are lost even before there are noticeable changes in kidney
histology, a condition referred to as minimal change nephropathy.
leading to albuminuria.
107. AFFERENT ARTERIOLE
(Divides into a tuft of
capillaries)
EFFERENT ARTERIOLE
Bowman’s capsule
GLOMERULAR
BASEMENT MEMBRANE
AND PODOCYTES
Bowman’s Space
Mesangial
cells
108. MESANGIAL CELLS
• provide structural support to the glomerular tuft, produce
and maintain mesangial matrix,
• The “mesangium” refers to the mesangial cells together
with the mesangial matrix they produce.
• act as phagocytes and remove trapped material from the
basement membrane of the capillaries.
• They also contain large numbers of myofilaments and can
contract in response to a variety of stimuli in a manner
similar to vascular smooth muscle cells.
109. Applied - Kidney diseases
(Nephropathies) and Filtration
Barrier
110. GLOMERULONEPHRITIS
• encompasses a subset of renal diseases characterized by immune-
mediated damage to the glomeruli leading to hematuria, proteinuria, and
azotemia
• inflammation of the capillary loops in the glomeruli of the kidney.
111. Clinical Significance of Proteinuria
• Early detection of renal disease in at-risk patients
• hypertension: hypertensive renal disease
• diabetes: diabetic nephropathy
• pregnancy: gestational proteinuric hypertension
(pre-eclampsia)
• annual “check-up”: renal disease can be silent
• Assessment and monitoring of known renal disease
112. Standard urinary dipstick
• Negative
• Trace — between 15 and 30 mg/dL
• 1+ — between 30 and 100 mg/dL
• 2+ — between 100 and 300 mg/dL
• 3+ — between 300 and 1000 mg/dL
• 4+ — >1000 mg/dL
Measurement of Urinary
Protein Excretion
Dipstick protein tests may not be very accurate:
“trace” results can be normal & positives must
be confirmed by quantitative laboratory test.
113. Microalbuminuria
• Definition: urine excretion of > 30 but < 150
mg albumin per day
• Causes: early diabetes, hypertension,
• Prognostic Value:
diabetic patients with microalbuminuria are 10-20
fold more likely to develop persistent proteinuria.
114. Glomerular filtration rate (GFR)
• amount of plasma ultrafiltrate formed each minute
• equal to the sum of the filtration rates of all the
functioning nephrons.
• Index of kidney function .
• essential for evaluating the severity and course of kidney
disease.
• A fall in GFR generally means that disease is progressing,
whereas an increase in GFR generally suggests recovery
115. Glomerular filtration rate (GFR)
• amount of plasma ultrafiltrate formed each minute
• equal to the sum of the filtration rates of all the
functioning nephrons.
• Index of kidney function .
• essential for evaluating the severity and course of kidney
disease.
• A fall in GFR generally means that disease is progressing,
whereas an increase in GFR generally suggests recovery
116. Normal GFR
• The GFR in a healthy person of average size is
approximately 125 mL/min.
• A rate of 125 mL/min is 7.5 L/h, or 180 L/d.
118. GFR Is About 20 Per Cent of the
Renal Plasma Flow
• about 20 per cent of the plasma flowing through the kidney is
filtered through the glomerular capillaries.
• The fraction of the renal plasma flow that is filtered (the filtration
fraction) averages about 0.2
Filtration fraction = GFR/Renal plasma flow
119. Renal blood flow
• High blood flow (~22% of cardiac output)
• High blood flow needed for high GFR
• Oxygen and nutrients delivered to kidneys
normally greatly exceeds their metabolic
needs
• A large fraction of renal oxygen consumption is
related to renal tubular sodium reabsorption
121. • The factors governing filtration across the glomerular
capillaries are the same as those governing filtration
across all other capillaries.
the size of the capillary bed
the permeability of the capillaries
the hydrostatic and osmotic pressure gradients across
the capillary wall
123. • Oncotic pressure, or colloid osmotic pressure, is a
form of osmotic pressure exerted by proteins,
notably albumin, in a blood vessel's plasma
(blood/liquid) that usually tends to pull water into
the circulatory system. It is the opposing force to
hydrostatic pressure.
• hydrostatic pressure in blood vessels is the pressure
of the blood against the wall. It is the opposing
force to oncotic pressure
133. Kf
• 12.5 ml/ mm Hg/ min / total glomeruli of total
renal substance of both kidneys
134. Kf
• 12.5 ml/ min / mm Hg / total glomeruli of total renal substance of both
kidneys
i.e., 4.2 ml/min/mm Hg/100 gm of renal substance
• the Kf of most other capillary systems of the body- 0.01
ml/min/mm Hg per 100 grams
135. • Normally not highly variable
• increased Kf raises GFR and decreased Kf
reduces GFR, changes in Kf probably do not
provide a primary mechanism for the
normal day-to-day regulation of GFR.
Kf
148. ▪Dia of afferent arteriole > efferent glom arteriole –
▪Capillary bed between two arteries–
2.Unique pressure dynamics within
the glomeruli
afferent
efferent
151. Glomerular Hydrostatic Pressure (PG)
• Is the determinant of GFR most subject
to physiological control
• Factors that influence PG
- arterial pressure (effect is buffered
by autoregulation)
- afferent arteriolar resistance
- efferent arteriolar resistance
154. Systemic B. P
• AP
tends to raise glomerular hydrostatic
pressure and, therefore, to increase GFR.
• Not much change in GFR-
autoregulatory mechanisms that
maintain a relatively constant glomerular
pressure as blood pressure fluctuates.
162. Kf GFR
PB GFR
PG GFR
PA PG
FF PG
PG GFR
RA PG
RE PG
Summary of Determinants of GFR
GFR
GFR
GFR
(as long as RE < 3-4 x normal)
163.
164. Determinants of Renal Blood
Flow (RBF)
RBF = P/R
P = difference between renal artery
pressure and renal vein pressure
R = total renal vascular resistance
= Ra + Re + Rv
= sum of all resistances in kidney
vasculature
171. To protect the glomerular capillaries from
hypertensive damage and to preserve a
healthy GFR at different arterial pressure
values, changes in GFR and RBF are
minimized by several mechanisms that we
collectively call autoregulation.
172. Autoregulation of RBF and
GFR
Myogenic mechanism
Tubuloglomerular
feedback mechanism
177. Macula densa
• Near the end of the
thick ascending limb,
the nephron passes
between the afferent
and efferent arterioles
of the same nephron.
• This short segment of the
thick ascending limb
abutting the glomerulus
is called the macula
densa
178.
179. The Juxtaglomerular cells (Granular
cells)
• specialized smooth
muscle cells
surrounding the
afferent arteriole
• Secrete Renin
180. The lacis cells (Extraglomerular mesangial cells)
• located in the space between
the afferent and efferent
arterioles OUTSIDE THE
GLOMERULUS
• pale staining, renin containing
cells
• a type of smooth muscle cell
• their function is yet to be fully
clarified
• they play a role in
autoregulation of blood flow to
the kidney and regulation of
systemic blood pressure
through the renin-angiotensin
system??
183. Autoregulation - Tubuloglomerular
feedback mechanism
Low Systemic B.P
Decreased GFR
slows the flow rate of filtrate
causing increased reabsorption of
sodium and chloride ions in the
ascending loop of Henle
Thereby reducing the concentration of
sodium chloride at the macula densa
cells.
184. Autoregulation- Tubuloglomerular
feedback mechanism
This decrease in sodium chloride
concentration initiates a signal from the macula
densa that has two effects
(1) the afferent arterioles dialatation,
(2) it increases renin
release from the juxtaglomerular cells
Finally, the angiotensin II constricts the efferent
arterioles,
186. HOW MACULA DENSA TRIGGERS
CHANGES AFFERENT ARTERIOLAR
RESISTANCE • An increase in the GFR elevates the [NaCl] in
tubule fluid at the macula densa.
• Na+ and Cl– enter the macula densa cells via the Na–
K–2Cl cotransporter
• increased Na, K ATPase activity
• increased ATP hydrolysis causes more adenosine is
formed.
• increase in adenosine triphosphate (ATP) and
adenosine (ADO) release
• ATP and adenosine binds to receptors in the
plasma membrane of smooth muscle cells
surrounding the afferent arteriole
• both of which increase intracellular [Ca++].
• afferent vasoconstriction and a resultant decrease in
GFR.
187. HOW MACULA DENSA TRIGGERS
CHANGES IN RENIN SECRETION
• that ATP and ADO also inhibit
renin release by granular cells
in the afferent arteriole.
• This action, too, results from
an increase in intracellular
[Ca++], reflecting electrical
coupling of the granular and
vascular smooth muscle
(VSM) cells
190. • the macula densa may release both
vasoconstrictors (e.g., ATP and
adenosine) and a vasodilator (e.g., NO),
which oppose each other’s action at the
level of the afferent arteriole. Production
plus release of
either vasoconstrictors or vasodilators
ensures exquisite control over
tubuloglomerular feedback.
191. 100 180 L/day 178.5 L/day 1.5 L/day
125 225 L/day 178.5 L/day 46.5 L/day
Importance of Autoregulation
Arterial GFR Reabsorption Urine
Pressure Volume
Poor Autoregulation + no change in tubular reabsorption
195. 1. Sympathetic Nervous System/catecholamines
RA + RE GFR + RBF
Control of GFR and renal blood flow
2. Angiotensin II
RE GFR + RBF
(prevents a decrease in GFR)
e.g. severe hemorrhage
e.g. low sodium diet, volume depletion
196. Control of GFR and renal blood flow
(cont’d)
3. Prostaglandins
RA + RE GFR + RBF
Blockade of prostaglandin synthesis → ↓ GFR
This is usually important only when there are
other disturbances that are already tending to
lower GFR
e.g. nonsteroidal anti-inflammatory drugs in a
volume depleted patient, or a patient with heart failure, etc
197. 4. Endothelial-Derived Nitric Oxide (EDRF)
RA + RE GFR + RBF
• Protects against excessive vasoconstriction
• Patients with endothelial dysfunction (e.g. atherosclerosis)
may have greater risk for excessive decrease in GFR in
response to stimuli such as volume depletion
Control of GFR and renal blood flow
(cont’d)
198. 5. Endothelin
RA + RE GFR + RBF
• Hepatorenal syndrome – decreased renal function
in cirrhosis or liver disease
• Acute renal failure
Endothelin antagonists may be useful in these conditions
Control of GFR and renal blood flow
(cont’d)
202. Hormones that Influence Glomerular
Filtration Rate and Renal Blood Flow
Sympathetic
nerves
Angiotensin II
Endothelin
Prostaglandins
(PGE1, PGE2, PGI2)
Nitric oxide
Bradykinin
EFFECT
ON GFR
EFFECT
ON RBF
↓ ↓
↑ ↓
↓ ↓
↑ ↑
↑ ↑
↑ ↑
203.
204.
205. Other Factors That Influence GFR
• Aging: decreases GFR 10%/decade after 40 yrs
• Hyperglycemia: increases GFR (diabetes mellitus)
• Dietary protein: high protein increases GFR
low protein decreases GFR
206. Possible role of macula
densa feedback in
increasing GFR after a
high protein meal
207.
208. Clearance
volume of plasma per unit time from
which all of a specific substance is
removed.
209. Renal Clearance
• Renal clearance of a substance is the volume of
plasma completely cleared of a substance
per min by the kidneys.
Note: Renal clearance means that the substance is
removed from the plasma and excreted in the urine.
210. If the plasma passing through the kidneys
contains 1 milligram of a substance in each
millilitre and if 1 milligram of this substance is
also excreted into the urine each minute, then
calculate the volume of plasma which is
“cleared” of the substance per minute…
211. If the plasma passing through the kidneys
contains 1 milligram of a substance in each
millilitre and if 1 milligram of this substance is
also excreted into the urine each minute, then 1
ml/min of the plasma is “cleared” of the
substance.
212. Renal Clearance
• Renal clearance of a substance is the volume of
plasma completely cleared of a substance
per min by the kidneys.
Note: Renal clearance means that the substance is
removed from the plasma and excreted in the urine.
213.
214. The concept of renal clearance is based on the
Fick’s principle (i.e., mass balance or
conservation of mass).
215. Clearance Technique
Amount cleared/Time = Amount in urine/Time
Cs x Ps = Us x V
Where : Cs = clearance of substance S
Ps = plasma conc. of substance S
Us = urine conc. of substance S
V = urine flow rate
Cs = Us x V = urine excretion rate s
Ps Plasma conc(s)
216. What is the clearance of a substance when its
concentration
in the plasma is 10 mg/dL, its concentration in the urine
is
100 mg/ dL, and urine flow is 2 mL/min?
A. 2 mL/min
B. 10 mL/min
C. 20 mL/min
D. 200 mL/min
E. Clearance cannot be determined from the information
given.
217. The volume of plasma cleared of inulin is the volume
filtered.
Therefore, inulin clearance equals the GFR.
218. For a substance that is freely filtered, but not reabsorbed or
secreted (inulin), renal clearance is equal to GFR
Use of Clearance to Measure GFR
amount filtered = amount excreted
GFR x Pin = Uin x V
GFR =
Pin
Uin x V
219. Calculate the GFR from the following data:
Pinulin = 1.0 mg / 100ml
Uinulin = 125 mg/100 ml
Urine flow rate = 1.0 ml/min
220. Calculate the GFR from the following data:
Pinulin = 1.0 mg / 100ml
Uinulin = 125 mg/100 ml
Urine flow rate = 1.0 ml/min
GFR =
125 x 1.0
1.0
= 125 ml/min
GFR = Cinulin =
Pin
Uin x V
221. INULIN
a polymer of fructose with a molecular weight of
about 5-kD
Nontoxic
not metabolized by the body
No plasma protein binding
Small molecule
freely filtered through the glomeruli
neither secreted nor reabsorbed by the tubules.
222. Clearance of creatinine
Clearance of creatinine can also be used to determine
GFR
however some creatinine is secreted by the tubules
thus the clearance of creatinine will be slightly
higher than inulin.
In spite of this, the clearance of endogenous creatinine
is a reasonable estimate of GFR as the values agree
quite well with the GFR values measured with inulin
223. Q. If the clearance of a substance which is freely
filtered is less than that of inulin,
A. there is net reabsorption of the substance in the
tubules.
B. there is net secretion of the substance in the tubules.
C. the substance is neither secreted nor reabsorbed in the
tubules..
E. the substance is secreted in the proximal tubule to a
greater
degree than in the distal tubule.
225. Theoretically, if a substance is completely cleared from
the plasma, its clearance rate would equal renal plasma flow
Use of Clearance to Estimate Renal Plasma Flow
Cx = renal plasma flow
226. Paraminohippuric acid (PAH) is freely filtered and secreted
and is almost completely cleared from the renal plasma
Use of PAH Clearance to Estimate Renal
Plasma Flow
1. amount enter kidney =
RPF x PPAH
3. ERPF x Ppah = UPAH x V
ERPF = UPAH x V
PPAH
ERPF = Clearance PAH
2. amount entered = amount excreted
~
~ 10 % PAH
remains
227. To calculate actual RPF , one must correct
for incomplete extraction of PAH
EPAH = APAH - VPAH
APAH
RPF =
ERPF
EPAH
normally, EPAH = 0.9
i.e., PAH is 90% extracted
APAH = 1.0
= 1.0 – 0.1
1.0
= 0.9
VPAH = 0.1
228. A patient is infused with paraaminohippuric acid
(PAH) to measure renal blood flow (RBF). She has a
urine flow rate of 1 mL/min, a plasma [PAH] of 1
mg/mL, a urine [PAH] of 600 mg/mL, and a hematocrit
of 45%. What is her “effective” RBF?
(A) 600 mL/min
(B) 660 mL/min
(C) 1091 mL/min
(D) 1333 mL/min
229. Clearances of Different Substances
Clearance of inulin (Cin) = GFR
if Cx < Cin: indicates reabsorption of x
Clearance of PAH (Cpah) ~ effective renal plasma flow
Substance Clearance (ml/min)
inulin 125
PAH 600
glucose 0
sodium 0.9
urea 70
Clearance creatinine (Ccreat) ~ 140 (used to estimate GFR)
if Cx > Cin: indicates secretion of x
230. Question
The maximum possible clearance rate of a
substance that is completely cleared from the
plasma by the kidneys would be equal to
1. glomerular filtration rate
2. the filtered load of the substance
3. urine excretion rate of the substance
4. renal plasma flow
5. none of the above
231. Effect of reducing GFR by
50 % on serum creatinine
concentration and
creatinine excretion rate
234. Which of the following substances has the
highest renal clearance?
(A) Para-aminohippuric acid (PAH)
(B) Inulin
(C) Glucose
(D) Na+
235. The following information was obtained in a 20-year-old
college student who was participating in a research study
in the Clinical Research Unit:
Plasma Urine
[Inulin] = 1 mg/mL [Inulin] = 150 mg/mL
[X] = 2 mg/Ml [X] = 100 mg/mL
Urine flow rate = 1
mL/min
Assuming that X is freely filtered, which of the following
statements is most correct?
(A) There is net secretion of X
(B) There is net reabsorption of X
(C) The clearance of X could be used to measure the
glomerular filtration rate (GFR)
(D) The clearance of X is greater than the clearance of
240. Tubular Reabsorption -Routes/ Pathways
• Transcellular pathway:
through the cells
• Paracellular pathway:
Around the cells, that is,
through the matrix of the
tight junctions
241. Tubular Cells –Tight Junctions
▪Tight junctions
link each epithelial cell to
its neighbor
▪Tight junctions –
claudins and occludins.
242.
243.
244. • Occlusive barrier
• Divide the cell membrane into discrete domains
.
• Physical separation allows cells to allocate
membrane proteins and lipids asymmetrically.
• Said to be polarized.
• Asymmetric assignment of proteins mediating
transport processes, provides the structural
machinery for the directional movement of fluid
and solutes by the nephron.
Tubular Cells –Tight Junctions
245. • Passive transport of
substances (without the
expenditure of external
energy):
Movement of any solute down
its electrochemical gradient
• Active transport of
substances (with the
expenditure of external
energy):
Movement of any solute
against its electrochemical
gradient
GENERAL PRINCIPLES OF MEMBRANE
TRANSPORT –across cell membranes
248. The presence or absence
of a given transport
protein endows the
tubular epithelium with
selectivity
It also applies to
paracellular flux through
tight junctions.
249. claudin family of protein,
determine the degree to which
various substances can travel
paracellularly.
In the proximal tubule, small
ions such as sodium and
potassium, water, and urea can
move by the paracellular route.
In the thick ascending limb,
sodium and potassium, but not
water
or urea, can move
paracellularly.
Neither location permits the
paracellular movement of
glucose
250. • High GFR :-
Fltered water and nonwaste
solutes are also very large.
• Primary role of the proximal
tubule :-
reabsorb much of this filtered
water and solutes.
• “Mass reabsorber.
• Also major site of solute secretion
“Division of Labor” in the Tubules
251. • Henle’s loop :-
Also reabsorbs relatively large
quantities of the major ions and, to a
lesser extent, water.
• Extensive reabsorption by PCT and
Henle’s loop ensures:-
masses of solutes and the volume of
water entering the tubular
segments beyond Henle’s loop are
relatively small.
“Division of Labor” in the Tubules
252. • Distal segments :-
fine-tuning for most substances
• Determines the final amounts
excreted in the urine by adjusting
their rates of reabsorption and, in
a few cases, secretion.
• Most homeostatic controls are
exerted.
“Division of Labor” in the Tubules
256. The proximal tubule
Reabsorbs
65 % Na+,
65 % Water
65 % of Cl-, K+, and other solutes
100 % Glucose
100% Amino acids
most of the HCO3
257. SOLUTE AND WATER REABSORPTION
ALONG THE NEPHRON :- Proximal
Tubule
• Reabsorbs approximately 65% of the filtered water, Na+, Cl-,
K+, and other solutes.
• In addition, the proximal tubule reabsorbs virtually all the
glucose and amino acids filtered by the glomerulus.
• The key element in proximal tubule reabsorption is the Na+,K+-
ATPase in the basolateral membrane
• Reabsorption of virtually all organic solutes, Cl-, other ions, and
water is coupled to Na+ reabsorption.
258. • Luminal edges (the urine side of the
cell) of the cells :-
Brush border
Only proximal tubule cells have this
brush border
• Basolateral membrane (the blood
side of the cell) :-
Highly invaginated.
These invaginations contain many
mitochondria
The proximal tubule
259. •The key element in proximal tubule
reabsorption is the Na+,K+-ATPase
in the basolateral membrane
260. In the proximal tubule the transport
of water and every solute is tied
directly or indirectly to the active
transport of sodium by the Na-K-
ATPase
261. Basic mechanism for active
transport of sodium
• Sodium-potassium pump :-
transports sodium from the
interior of the cell across the
basolateral membrane:-
creating a low intracellular
sodium concentration and a
negative intracellular electrical
potential.
• Cause sodium ions to diffuse
from the tubular lumen into the
cell through the brush border.
267. Na+ reabsorption :-First half of
proximal tubule
• Na+ is reabsorbed primarily with HCO3
- and, to a
lesser degree,a number of organic molecules (e.g.,
glucose, amino acids)
270. • Late proximal tubule :-
very little glucose and amino
acids
But has a high concentration of
Cl-
• High Cl- concentration is due to
the preferential reabsorption of
Na+ with HCO3
- and organic
solutes in the early proximal
tubule
Concentration of solutes in tubular fluid as a function of length
along the proximal tubule
271. Second half of proximal tubule
Na+ and Cl-reabsorption
Transcellular
Paracellular
272. • Late proximal tubule have
different Na+ transport
mechanisms.
• Operation of parallel Na+-H+ and
Cl--anion antiporters.
• Secreted H+ and anion combine in
the tubular fluid and re-enter the
cell
• Operation of the Na+-H+ and Cl-
anion antiporters is equivalent to
NaCl uptake from tubular fluid
into the cell.
Na+ and Cl- reabsorption :-
Second half of proximal tubule
273. • Paracellular NaCl reabsorption
Rise in [Cl-] in the tubular fluid in the
early proximal tubule
Diffusion of Cl- from the tubular lumen
across the tight junctions into the
lateral intercellular space.
• Tubular fluid become positively
charged relative to the blood.
• Positive transepithelial voltage causes
the diffusion of Na+ out of the tubular
fluid across the tight junctions.
Na+ reabsorption :-Second half of
proximal tubule
274. Mechanisms by which water, chloride,
and urea reabsorption are coupled with
sodium reabsorption – Second half of
proximal tubule
275.
276. Second half of proximal tubule
• Na+-glucose symporter
(SGLT1)
278. Water reabsorption - Osmosis
• When solutes are transported out of
the tubule their concentrations tend
to decrease inside the tubule while
increasing in the renal interstitium.
• This creates a concentration
difference that causes osmosis of
water in the same direction that the
solutes are transported,
• proximal tubule, are highly
permeable to water,
• water reabsorption occurs rapidly
279. Water reabsorption - Osmosis
• Some solutes, especially K+ and
Ca2+, are carried along in the
reabsorbed fluid
solvent drag
281. • [TF/P]x is the concentration of substance X in tubular fluid
relative to the concentration in plasma.
282. [TF/P]X = 1.0. X has not been reabsorbed or secreted (all freely
filtered substances in Bowman's space), or X is reabsorbed in
proportion to water (e.g., Na in proximal tubule)
[TF/P]X < 1.0. X is reabsorbed more than water
[TF/P]X > 1.0. X is reabsorbed less than water or X is secreted
285. Osmolarity, remains essentially the
same all along the proximal tubule
• the summed total of
solutes (osmoles)
reabsorbed is
proportional to water
reabsorbed.
• called iso-osmotic
reabsorption.
286. Protein reabsorption :- Proximal tubule
• peptide hormones, small proteins, and even small amounts of larger
proteins, such as albumin, are filtered by the glomerulus.
partially degraded by enzymes on the surface of the proximal tubule
cells.
taken into the cell by endocytosis.
enzymes digest the proteins and peptides into their constituent amino
acids
Amino acids then exit the cell across the basolateral membrane and
return to the blood.
289. Secretion in proximal tubule
• Creatinine
• Bile salts
• Oxalate
• Urate
• catecholamine
• Various drugs & Toxins
• PAH
290.
291.
292. • Many organic anions compete for the same secretory
pathways
• Similar competition is observed for organic cation
secretion by the proximal tubule
293. • At which site is about one-third of the filtered water
remaining in the tubular fluid?
(A) Site A
(B) Site B
(C) Site C
(D) Site D
(E) Site E
294. • Water channel present in proximal convoluted tubule is:
1. Aquaporin 1
2. Aquaporin 2
3. Aquaporin 3
4. Aquaporin 4
• At the leaving end of proximal convoluted tubule , percentage of
filtered solute and water is approximately:
1) 35% solute and 35% water
2) 45%solute and 45% water
3) 35% solute and 45% water
4) 45%solute and 35% water
295. • Percentage of filtered urea, reabsorbed by Proximal tubule is
about:
1. 00-20
2. 50 -60
3. 70-95
4. 80-100
296. • In the presence of ADH, the greatest fraction of filtered water is absorbed in the
A. proximal tubule.
B. loop of Henle.
C. distal tubule.
D. cortical collecting duct.
E. medullary collecting duct.
• In the absence of ADH, the greatest fraction of filtered water is absorbed in the
A. proximal tubule.
B. loop of Henle.
C. distal tubule.
D. cortical collecting duct.
E. medullary collecting duct.
297. The proximal tubule
Reabsorbs
65 % Na+,
65 % Water
65 % of Cl-, K+, and other solutes
100 % Glucose
100% Amino acids
most of the HCO3
298. Limits on Rate of Transport: Tubular
transport maximum (Tm) and Gradient-
limited Systems
The classification is based on the leakiness of the tight
junctions
299. The rate of reabsorption for any
substance is limited by the capacity
of the transporters (Tm systems) or
by paracellular back leak (gradient-
limited)
301. Gradient-limited systems.
When the tight junctions are very leaky to a given
substance, for example, sodium, it is impossible for
the removal of the substance from the lumen to
reduce its luminal concentration very much below
that in the renal interstitium.
As the substance is removed and the luminal
concentration starts to fall, the gradient between
these 2 media increases, causing the substance to
leak back as fast as it is removed (like bailing a very
leaky boat)
303. Tm-limited systems: In this case the tight
junctions are impermeable to the solutes in
question. There is no back leak and no limit
on the size of the difference in
concentration between lumen and
interstitium.
304. Transport Maximum for Substances That Are
Actively Reabsorbed.
A limit to the rate at which the
solute can be transported
This limit is due to saturation of the specific
transport systems involved when the amount of
solute delivered to the tubule exceeds the capacity of
the carrier proteins and specific enzymes involved in
the transport
305.
306. Glucose transport system in the proximal tubule
Transport maximum for glucose averages
about 375 mg/min
Normal Filtered load of glucose is only about
125 mg/min at plasma glucose conc
100mg/100ml
no loss of glucose in the urine
However, when the plasma concentration,of
glucose rises above about 200 mg/100 ml,
increasing the filtered load to about 250
mg/min,
A small amount of glucose begins to appear in
the urine.
This point is termed the threshold for glucose.
This appearance of glucose in the urine (at the
threshold) occurs before the transport maximum
is reached.
307. Glucose transport system in the proximal tubule
One reason for the
difference between
threshold and
transport maximum is
that not all nephrons
have the same
transport maximum
for glucose.
308. Cause of difference of TmG and Renal threshold for glucose
Phenomenon of SPLAY
Rate of
glucose
reabsorption
reaches the
Tm
gradually,
not abruptly.
The rate of glucose
reabsorption
reaches a plateau—
the transport
maximum (Tm)—at
~ 375 mg/min
309. Splay in titration curve
Reflects both anatomical and kinetic differences among
nephrons.
Therefore, a particular nephron's filtered load of glucose may
be mismatched to its capacity to reabsorb glucose.
For example, a nephron with a larger glomerulus has a larger
load of glucose to reabsorb.
Different nephrons may have different distributions and
densities of SGLT2 and SGLT1 along the proximal tubule.
Accordingly, saturation in different nephrons may occur at
different plasma levels
310. Cause of difference of TmG and Renal threshold for glucose
Phenomenon of SPLAY
311. Transport maximums for substances actively
reabsorbed
Substance Transport Maximum
Glucose 375 mg/min
Phosphate 0.10 mM/min
Sulfate 0.06 mM/min
Amino acids 1.5 mM/min
Urate 15 mg/min
Lactate 75 mg/min
Plasma protein 30 mg/min
312.
313. Q. At plasma concentrations of glucose higher than
occur at transport maximum (Tm), the
(A) clearance of glucose is zero
(B) excretion rate of glucose equals the filtration rate of glucose
(C) reabsorption rate of glucose equals the filtration rate of
glucose
(D) excretion rate of glucose increases with increasing plasma
glucose concentrations
(E) renal vein glucose concentration equals the renal artery
glucose concentration
316. Fanconi syndrome
Results from an impaired ability of the proximal tubule
to reabsorb HCO3 , amino acids, glucose, and low-
molecular-weight proteins.
results in increased urinary excretion of HCO3–, amino
acids, glucose, and low-molecular-weight proteins
317. SOLUTE AND WATER REABSORPTION ALONG
THE NEPHRON :- Henle’s loop
318.
319. SOLUTE AND WATER REABSORPTION ALONG THE
NEPHRON :- Henle’s loop
Loop of Henle reabsorbs approximately 15% of the
filtered water.
Water reabsorption occurs exclusively in the descending
thin limb. The ascending limb is impermeable to water.
Reabsorbs approximately 25% of the
filtered NaCl and K+
Ca2+ and HCO3
- are also reabsorbed in the loop of Henle .
Solute reabsorption occurs mostly in the thick ascending limb.
325. Solute reabsorption :- Thick ascending limb
key element in solute
reabsorption is the
Na+,K+-ATPase in the
basolateral membrane
Movement of Na+ across the apical
membrane into the cell is mediated
by the 1Na+-1K+-2Cl- symporter.
Using the potential energy released
by the downhill movement of Na+
and Cl-, this symport drives the uphill
movement of K+ into the cell.
326. Solute reabsorption :- Thick ascending limb
a slight backleak of potassium
ions into the lumen,
a positive charge of about +8
millivolts in the tubular
lumen.
This positive charge forces
cations such as Mg++ and
Ca++ to diffuse from the
tubular lumen through the
paracellular space and into
the interstitial fluid
328. SOLUTE AND WATER REABSORPTION ALONG THE
NEPHRON :- Henle’s loop
Loop of Henle reabsorbs approximately 15% of the
filtered water.
Water reabsorption occurs exclusively in the descending
thin limb. The ascending limb is impermeable to water.
Reabsorbs approximately 25% of the
filtered NaCl and K+
Ca2+ and HCO3
- are also reabsorbed in the loop of Henle .
Solute reabsorption occurs mostly in the thick ascending limb.
331. Applied -Bartter Syndrome
Mutations in the gene coding for the Na+-
K+-2Cl− symporter (NKCC)→ hypokalaemia,
metabolic alkalosis, and hyperaldosteronism
332. Tubular Lumen
Tubular Cells
Bartter’s Syndrome: Decreased Activity of Na-K-2Cl
Co-Transporter in Thick Ascending Loop of Henle
Na+
ATP
Cl-
K+
K+
Cl-
Na+
ATP
H2O
Bartter’s Syndrome:
K+
Na+
H+
333. SOLUTE AND WATER REABSORPTION ALONG THE
NEPHRON :-Distal Tubule and Collecting Duct
reabsorb approximately 8% of the filtered NaCl,
secrete variable amounts of K+ and H+
Reabsorb a variable amount of water (∼8% to
17%).
Water reabsorption depends on the
plasma concentration of ADH.
334. The initial segment of the distal tubule (the early distal
tubule) reabsorbs Na+, Cl–, and Ca++ and is impermeable
to water
336. Early Distal Tuble
avidly reabsorbs most of the ions,
including sodium, and chloride
virtually impermeable to water
~5 percent of the filtered load of
sodium chloride is reabsorbed
The sodium-chloride co-transporter
moves sodium chloride from the
tubular lumen into the cell.
338. Tubular Lumen
Tubular Cells
Gitleman’s Syndrome: Decreased NaCl
Reabsorption in Early Distal Tubule
Na+
ATP
Cl-
K+
Cl-
Na+
ATP
H2O
Gitleman’s
Syndrome:
339. Late Distal Tubule, Cortical
Collecting Tubule and Outer medullary collecting duct
similar functional characteristics.
two distinct cell types, the
principal cells and the
intercalated cells
Principal cells reabsorb Na+
and water and secrete K+.
Intercalated cells either secrete H+
(reabsorb HCO3
-) or secrete HCO3
-
(reabsorb H+) and thus are important in
regulating acid-base balance.
340. Transport pathways in intercalated cells - type A
secrete hydrogen ions by a
hydrogen-ATPase
transporter and by a
hydrogen-
potassium-ATPase
transporter.
341. Transport pathways in intercalated cells - type A
Hydrogen ion secretion is accomplished in
two steps:
(1) the dissolved CO2 in this cell combines
with H2O to form H2CO3 , and
(2) the H2CO3 then dissociates into HCO3 −
, which is reabsorbed into the blood, plus H+ ,
which is secreted into the tubule
For each H+ secreted, an HCO3 − is
reabsorbed
Type A intercalated cells are especially
important in eliminating hydrogen ions while
reabsorbing bicarbonate in acidosis
342.
343. Type B intercalated cells have functions
opposite to those of type A cells and
secrete bicarbonate into the tubular
lumen while reabsorbing hydrogen ions
in alkalosis.
345. Transport pathways in principal cells
Sodium reabsorption and
potassium secretion by the
principal cells depend on the
activity of a sodium-
potassium ATPase
pump in each cell’s
basolateral membrane.
This pump maintains a low sodium
concentration inside the cell and,
therefore, favors sodium diffusion
into the cell through special channels
[epithelial Na+-selective
channels (ENaCs)]
346. Transport pathways in principal cells
The secretion of potassium by
these cells involves two steps:
(1) potassium enters the cell
because of the sodium-potassium
ATPase pump, which maintains a
high intracellular potassium
concentration, and then
(2) once in the cell, potassium
diffuses down its concentration
gradient across the luminal
membrane into the tubular fluid.
351. Aldosterone actions on late distal, cortical and
medullary collecting tubules
• Increases Na+ reabsorption - principal cells
• Increases K+ secretion - principal cells
• Increases H+ secretion - intercalated cells
352. Late Distal, Cortical and Medullary
Collecting Tubules
Tubular Lumen
Principal Cells
Cl-
H20 (+ ADH)
Aldosterone
K+
Na+
ATP
K+
ATP
Na+
353. Aldosterone enhances the reabsorption of NaCl
across principal cells by:
activation of ENaCs
activation of Na+-K+-ATPase
increasing amount of the sodium channel (ENaC) in the
apical cell membrane;
increasing the amount of Na+-K+-ATPase in the
basolateral membrane;
360. INNER MEDULLARY COLLECTING DUCT
Unlike the cortical collecting tubule, the medullary
collecting duct is permeable to urea, and there are special urea
transporters that facilitate urea diffusion across the luminal and basolateral
membranes.
Therefore, some of the tubular urea is reabsorbed into the medullary
interstitium, helping to raise the osmolality in this region of the
kidneys and contributing to the kidneys’ overall ability to form concentrated
urine.
361. Urea recycle
There are special urea
transporters ( UT A1 and UT A3)
that facilitate urea diffusion across
the luminal and Basolateral
membrane.
364. Concentrations of solutes in different parts of the
tubule depend on relative reabsorption of the
solutes compared to water
• If water is reabsorbed to a greater extent than the
solute, the solute will become more concentrated in
the tubule (e.g. creatinine, inulin)
• If water is reabsorbed to a lesser extent than the
solute, the solute will become less concentrated in
the tubule (e.g. glucose, amino acids)
365. The figure below shows the concentrations of inulin at different points
along the tubule, expressed as the tubular fluid/plasma (TF/Pinulin)
concentration of inulin. If inulin is not reabsorbed by the tubule, what is the
percentage of the filtered water that has been reabsorbed or remains at each
point ? What percentage of the filtered water has been reabsorbed up to that
point?
A =
B =
C =
A
3.0
B
8.0
C 50
366. The figure below shows the concentrations of inulin at different points
along the tubule, expressed as the tubular fluid/plasma (TF/Pinulin)
concentration of inulin. If inulin is not reabsorbed by the tubule, what is
the percentage of the filtered water that has been reabsorbed or remains at
each point? What percentage of the filtered water has been reabsorbed up
to that point?
A =
B =
C =
A
3.0
B
8.0
C 50
1/3 (33.33 %) remains
66.67 % reabsorbed
1/8 (12.5 %) remains
87.5 % reabsorbed
1/50 (2.0 %) remains
98.0 % reabsorbed
367. Secretion of K+ by the distal tubule will be decreased
by
(A) hyperaldosteronism
(B) spironolactone administration
(C) thiazide diuretic administration
(D) None of the above
368. If a diuretic that inhibits NaCl reabsorption (e.g.,
furosemide) in the thick ascending limb was given to
an individual, what would happen to water
reabsorption by this segment?
1. Decrease
2. Increase
3. No effect
384. Glomerulotubular balance :- Reduces the impact of GFR
changes on the amount of Na+ and water excreted in the
urine.
An increase in GFR causes an increase in the reabsorption of
solutes, and consequently of water, primarily in the proximal
tubule, so that in general the percentage of the solute
reabsorbed is held constant
a constant fraction of the filtered Na+
and water is reabsorbed from the
proximal tubule despite variations in
GFR.
386. an increase in GFR (at constant RPF) raises
the protein concentration in the glomerular
capillary plasma above normal.
This protein-rich plasma leaves the glomerular
capillaries, flows through the efferent arteriole,
and enters the peritubular capillaries
The increased oncotic pressure in the
peritubular capillaries augments the
movement of solute and fluid from the
lateral intercellular space into the
peritubular capillaries
This action increases net solute and
water reabsorption by the proximal
tubule.
Two mechanisms are responsible for G-T balance :- One is related to
the Starling forces
387. Second mechanism
Initiated by an increase in the filtered load of glucose and amino acids.
Reabsorption of Na+ in the early proximal tubule is coupled to that of glucose
and amino acids.
The rate of Na+ reabsorption therefore depends in part on the
filtered load of glucose and amino acids.
As GFR and the filtered load of glucose and amino acids increase, Na+ and
water reabsorption also rise
397. Antidiuretic Hormone (ADH)
• Increases H2O permeability and reabsorption in
distal and collecting tubules
• Allows differential control of H2O and solute excretion
• Important controller of extracellular fluid osmolarity
• Secreted by posterior pituitary
398. Figure 29-10
ADH synthesis in
the magnocellular
neurons of hypothalamus,
release by the posterior
pituitary, and action
on the kidneys
402. Atrial natriuretic peptide
increases Na+ excretion
• Secreted by cardiac atria in response to stretch
(increased blood volume)
• Directly inhibits Na+ reabsorption
• Inhibits renin release and aldosterone formation
• Increases GFR
• Helps to minimize blood volume expansion
403. Atrial Natriuretic Peptide (ANP)
Blood volume
Renal Na+ and H2O reabsorption
Renin release aldosterone GFR
Ang II
Na+ and H2O excretion
ANP
404. Parathyroid hormone increases
renal Ca++ reabsorption
• Released by parathyroids in response to
decreased extracellular Ca++
• Increases Ca++ reabsorption by kidneys
• Increases Ca++ reabsorption by gut
• Decreases phosphate reabsorption
• Helps to increase extracellular Ca++
405. Control of Ca++ by Parathyroid
Hormone
Extracellular
[Ca++]
PTH
Renal Ca++
Reabsorption
Intestinal Ca++
Reabsorption
Ca++ Release
From Bones
Vitamin D3
Activation
409. Sympathetic nervous system
increases Na+ reabsorption
• Directly stimulates Na+ reabsorption
• Stimulates renin release
• Decreases GFR and renal blood flow
(only a high levels of sympathetic
stimulation)
417. Aldosterone leads to Na+ retention and hence volume
expansion.
Eventually, the pressure natriuresis raises Na+ excretion
toward prealdosterone levels.
Thus, the kidney can escape the Na+-retaining effect of
aldosterone, albeit at the price of expanding the extracellular
volume and causing hypertension
418. Osmotic Effects on Reabsorption
• Water is reabsorbed only by osmosis
• Increasing the amount of unreabsorbed solutes
in the tubules decreases water reabsorption
i.e., diabetes mellitus: unreabsorbed glucose in
tubules causes diuresis and water loss
i.e., osmotic diuretics (mannitol)
420. Which of the following causes increased
aldosterone secretion?
(A) Decreased blood volume
(B) Administration of an inhibitor of
angiotensin-converting enzyme (ACE)
(C) Hyperosmolarity
(D) Hypokalemia
Which diuretic inhibits Na+ reabsorption
and K+ secretion in the distal tubule by
acting
as an aldosterone antagonist?
(A) Acetazolamide
(B) Chlorothiazide
(C) Furosemide
(D) Spironolactone
427. • Continue electrolyte
reabsorption
• Decrease water
reabsorption
Mechanism:
Decreased ADH release
and reduced water
permeability in distal
and collecting
tubules
Formation of a dilute urine
428. Concentration and Dilution of the Urine
• Maximal urine concentration
= 1200 - 1400 mOsm / L
• Minimal urine concentration
= 50 - 70 mOsm / L
429. Formation of a Concentrated Urine when
antidiuretic hormone (ADH) are high.
430. Formation of a Concentrated Urine when
antidiuretic hormone (ADH) are high.
431. REQUIREMENTS for forming
concentrated urine
A high level of ADH
which increases the permeability of the distal tubules
and collecting ducts to water, thereby allowing these
tubular segments to avidly reabsorb water
A high osmolarity of the renal
medullary interstitial fluid
which provides the osmotic gradient necessary for
water reabsorption to occur in the presence of high
levels of ADH.
434. Gradient of increasing osmolality along the medullary
pyramids.
Produced by the operation of the
loops of Henle as countercurrent
multipliers & Urea recycling
Maintained by the operation of
the vasa recta as countercurrent
exchangers.
435. • A countercurrent system is a system in which
the inflow runs parallel to, counter to, and in
close proximity to the outflow for some
distance.
• This occurs for both the loops of Henle and
the vasa recta in the renal medulla
439. Countercurrent Multiplication
• Countercurrent multiplication is the process in which a small gradient
established at any level of the loop of Henle is increased (multiplied) into
a much larger gradient along the axis of the loop.
• The operation of each loop of Henle as a countercurrent multiplier
depends on
(a)the high permeability of the thin descending limb to water .
(b) the active transport of Na+ and Cl– out of the thick ascending limb
(c)the inflow of isotonic tubular fluid from the proximal tubule, with
outflow of hypotonic fluid into the distal tubule.
440. UREA RECYCLE: Recirculation of Urea from the Collecting Duct
to the Loop of Henle Contributes to Hyperosmotic Renal Medulla.
441. Urea recycle
There are special urea
transporters ( UT A1 and UT A3)
that facilitate urea diffusion across
the luminal and Basolateral
membrane.
442. Urea Recirculation
• Urea is passively reabsorbed in proximal tubule
(~ 50% of filtered load is reabsorbed)
• In the presence of ADH, water is reabsorbed in
distal and collecting tubules, concentrating
urea in these parts of the nephron
• The inner medullary collecting tubule is highly
permeable to urea, which diffuses into the
medullary interstitium
• ADH increases urea permeability of medullary
collecting tubule by activating urea transporters (UT A1 and UT A3)
443. UREA CONTRIBUTES TO HYPEROSMOTIC
RENAL MEDULLARY INTERSTITIUM AND
FORMATION OF CONCENTRATED URINE
• Urea contributes about 40 to 50 per cent of the
osmolarity (500-600 mOsm/L) of the renal
medullary interstitium when the kidney is forming
a maximally concentrated urine.
• When there is water deficit and blood
concentrations of ADH are high, large amounts of
urea are passively reabsorbed from the inner
medullary collecting ducts into the interstitium.
444. Formation of a concentrated urine when
antidiuretic hormone (ADH) levels are high.
445. The Vasa Recta Preserve
Hyperosmolarity of Renal Medulla
446. • The vasa recta serve
as countercurrent
exchangers
Figure 29-7
The Vasa Recta Preserve Hyperosmolarity of
Renal Medulla
• Vasa recta blood
flow is low (only 1-2
% of total renal blood
flow)
447. • Blood towards medulla
progressively more concentrated,
partly by solute entry from the
interstitium and partly by loss of
water into the interstitium
• As blood ascends back toward the
cortex, it becomes progressively
less concentrated as solutes diffuse
back out into the medullary
interstitium and as water moves
into the vasa recta
448. • The vasa recta do not create the
medullary hyperosmolarity, but
prevent it from being dissipated.
• The u-shaped structure of the vessels
minimizes loss of solute from the
interstitium
.
449. HOW POSTERIOR PITUTARY COMES TO
KNOW THE SITUATION TO INCREASE OR
DECREASE ADH SECRETION?
461. Summary of water reabsorption and
osmolarity in different parts of the tubule
• Proximal Tubule: 65 % reabsorption, isosmotic
• Desc. loop: 15 % reasorption, osmolarity increases
• Asc. loop: 0 % reabsorption, osmolarity decreases
• Early distal: 0 % reabsorption, osmolarity decreases
• Late distal and coll. tubules: ADH dependent
water reabsorption
• Medullary coll. ducts: ADH dependent water
reabsorption
462. “Free” Water Clearance (CH2O)
(rate of solute-free water excretion)
Free-water clearance (CH2O) is
calculated as the difference
between water excretion (urine
flow rate) and osmolar clearance
463. Osmolar clearance (The total clearance of
solutes from the blood)
If plasma osmolarity is 300 mOsm/L, urine osmolarity is 600
mOsm/L, and urine flow rate is 1 ml/min,
How many ml of plasma are being cleared of solute each
minute?
The total clearance of solutes from the blood can be expressed
as the osmolar clearance (Cosm);
464. Clearance Technique
Amount cleared/Time = Amount in urine/Time
Cs x Ps = Us x V
Where : Cs = clearance of substance S
Ps = plasma conc. of substance S
Us = urine conc. of substance S
V = urine flow rate
Cs = Us x V = urine excretion rate s
Ps Plasma conc(s)
465. “Free” Water Clearance (CH2O)
(rate of solute-free water excretion)
Free-water clearance (CH2O) is
calculated as the difference
between water excretion (urine
flow rate) and osmolar clearance
466. CH2O = V - Uosm x V
Posm
where:
Uosm = urine osmolarity
V = urine flow rate
P = plasma osmolarity
If: Uosm < Posm, CH2O = +
If: Uosm > Posm, CH2O = -
rate of
free-water
clearance
represents
the rate at
which
solute-free
water is
excreted
by the
kidneys
“Free” Water Clearance (CH2O)
(rate of solute-free water excretion)
467. Question
Given the following data, calculate “free water”
clearance :
urine flow rate = 6.0 ml/min
urine osmolarity = 150 mOsm /L
plasma osmolarity = 300 mOsm / L
Is free water clearance in this example positive
or negative ?
468. Answer
CH2O = V - Uosm x V
Posm
= 6.0 - ( 150 x 6 )
300
= 6.0 - 3.0
= + 3.0 ml / min (positive)
469. Concentration and Dilution
of the Urine
• Maximal urine concentration
= 1200 - 1400 mOsm / L
• Minimal urine concentration
= 50 - 70 mOsm / L
470. Obligatory Urine Volume
The minimum urine volume in which the excreted
solute can be dissolved and excreted
471. Example:
If the max. urine osmolarity is 1200 mOsm/L,
and 600 mOsm of solute must be excreted each
day to maintain electrolyte balance, the
obligatory urine volume is:
600 mOsm/d
1200 mOsm/L
= 0.5 L/day
473. Clinical Implications
Diabetes insipidus:
results when there is a vasopressin deficiency or
inability of the kidneys to respond to vasopressin.
Symptoms of diabetes insipidus:
Polyuria
Polydipsia
Central Diabetes Insipidus.
Nephrogenic Diabetes Insipidus.
474. Disorders of Urine Concentrating Ability
• Failure to produce ADH :
“Central” diabetes insipidus
• Failure to respond to ADH:
“nephrogenic” diabetes insipidus
- impaired loop NaCl reabs. (loop diuretics)
- drug induced renal damage: lithium, tetracyclines
- kidney disease: pyelonephritis, hydronephrosis,
chronic renal failure
- malnutrition (decreased urea concentration)
475. In either case, large volumes of dilute urine are formed, which
tends to cause dehydration unless fluid intake is increased by
the same amount as urine volume is increased.
476. Lack of a prompt decrease in urine volume and an increase in
urine osmolarity within 2 hours after injection of desmopressin
is strongly suggestive of nephrogenic diabetes insipidus.
481. The kidneys minimize fluid loss during water deficits through
the osmoreceptor-ADH feedback system.
Adequate fluid intake, however, is necessary to counterbalance
whatever fluid loss does occur through sweating and breathing
and through the gastrointestinal tract.
Fluid intake is regulated by the thirst mechanism
487. Consequences of Hyponatremia
and Hypernatremia
• Water moves in and out of cells
cells swell (hyponatremia) or shrink
(hypernatremia)
• This has profound effects on the brain.
- Neurologic function is altered (confusion, seizures)
- Rapid shrinking can tear vessels and cause hemorrhage.
- Rapid swelling can cause herniation.
Because the skull is rigid, the brain cannot
increase its volume by more than 10 % without
being forced down the neck (herniation).
488. Effects of acute and
chronic hyponatremia
on the brain
Do not correct too rapidly –can cause brain
shrinkage
Treat with great caution!!
489. 40
300
200
100
0
0 10 20 30
OSMOLARITY
mOsm/L
Normal State
VOLUME (L)
ECF
ICF
1.
2.
3.
Effect of adding 2 L of 0.9 % NaCl ?
490. 40
300
200
100
0
0 10 20 30
OSMOLARITY
mOsm/L
Normal State
VOLUME (L)
ECF
ICF
1.
2.
3.
Effect of adding 2 L of 0.9 % NaCl ?
491. 40
300
200
100
0
0 10 20 30
OSMOLARITY
mOsm/L
Normal State
VOLUME (L)
ECF
ICF
1.
2.
3.
Effect of adding 2 L of 5 % Glucose (isosmotic)?
492. 40
300
200
100
0
0 10 20 30
OSMOLARITY
mOsm/L
Normal State
VOLUME (L)
ECF
ICF
1.
2.
3.
Instantaneously
Effect of adding 2 L of 5 % Glucose (isosmotic)?
493. 40
300
200
100
0
0 10 20 30
OSMOLARITY
mOsm/L
Normal State
VOLUME (L)
ECF
ICF
1.
2.
3.
Effect of adding 2 L of 5 % Glucose (isosmotic)?
Instantaneously
After metabolism of glucose
494. 40
300
200
100
0
0 10 20 30
OSMOLARITY
mOsm/L
Normal State
VOLUME (L)
ECF
ICF
1.
2.
3.
Effect of adding 2 L of 3 % NaCl ?
495. 40
300
200
100
0
0 10 20 30
OSMOLARITY
mOsm/L
Normal State
VOLUME (L)
ECF
ICF
1.
2.
3.
Effect of adding 2 L of 3 % NaCl ?
496. What are the Changes in the
following variables after giving
2.0 liters of 3% NaCl i.v. ?
Extracellular Fluid Volume ?
Extracellular Fluid Osmolarity ?
Intracellular Fluid Volume ?
Intracellular Fluid Osmolarity ?
> 2.0 Liters
517. The most important stimuli for aldosterone are
(1) increased extracellular potassium concentration and
(2) increased angiotensin II levels, which typically occur in conditions
associated with sodium and volume depletion or low blood pressure.
521. Parathyroid hormone increases
renal Ca++ reabsorption
• Released by parathyroids in response to
decreased extracellular Ca++
• Increases Ca++ reabsorption by kidneys
• Increases Ca++ reabsorption by gut
• Decreases phosphate reabsorption
• Helps to increase extracellular Ca++
526. Micturition
a process by which the urinary bladder
empties itself when it becomes filled.
It is a complete autonomic spinal reflex to get
urine outside the body, that is facilitated or
inhibited by higher brain centres (in adults).
532. Principal nerve supply of the bladder is by way of
the pelvic nerves (S-2, S-3, S-4)
both sensory nerve fibers and motor nerve fibers.
The sensory fibers detect the degree of stretch in
the bladder wall.
The motor nerves transmitted in the pelvic nerves
are parasympathetic fibers.
