Transcript Chapter 27:

Urine Formation by the Kidneys
II. Tubular Reabsorption and
Secretion
L3-L4-L5
1
Objectives

To understand the principle of Clearance and its
applications

To describe the mechanism of tubular reabsorption and
secretion.

To follow up the reabsorption of glomerular filtrate
along the tubules.

To understand the regulation of tubular reabsorption
and secretion.
2
Basic Mechanisms
of
Urine Formation
3
Clearance
• “Clearance” describes the rate at which substances
are removed (cleared) from the plasma.
• Renal clearance of a substance is the volume of
plasma completely cleared of a substance
per min by the kidneys.
4
Renal Clearance

Definition: The volume of plasma completely cleared of a substance (x)

per minute
Units are ml/min

Clearance,
Ux  V
C
Px
Uinulin  V
Cinulin 
Pinulin
Uinulin  V
GFR 
Pinulin
UX= Concentration of X in the urine (mg/ml)
PX= concentration of X in the plasma (mg/ml)
V= urine flow rate (ml/min)
CInulin – is equal to the GFR.(Glomerular Marker) Inulin is a
Fructose polymer ; freely filtered across the membrane and
neither reabsorbed nor secreted.
Clearance Technique
Renal clearance (Cs) of a substance is the volume of
plasma completely cleared of a substance per min.
Cs
Where :
Cs x Ps = Us x V
= Us x V = urine excretion rate s
Ps
Plasma conc. s
Cs = clearance of substance S
Ps = plasma conc. of substance S
Us = urine conc. of substance S
V = urine flow rate
6
Clearances of Different Substances
Substance
glucose
albumin
sodium
urea
inulin
creatinine
PAH
Clearance (ml/min)
0
0
0.9
70
125
140
600
7
Use of Clearance to Measure GFR
For a substance that is freely filtered, but not reabsorbed
or secreted (inulin, 125 I-iothalamate, creatinine), renal
clearance is equal to GFR
amount filtered = amount excreted
GFR x Pin
= Uin x V
GFR =
Uin x V
Pin
8
Calculate the GFR from the following data:
Pinulin = 1.0 mg / 100ml
Uinulin = 125 mg/100 ml
Urine flow rate = 1.0 ml/min
U
x
V
in
GFR = Cinulin =
Pin
GFR =
125 x 1.0 = 125 ml/min
1.0
9
Use of Clearance to Estimate Renal
Theoretically,
if a substance
is completely cleared
Plasma
Flow
from the plasma, its clearance rate would equal
renal plasma flow
Cx = renal plasma flow
10
Use of PAH Clearance to Estimate Renal
Plasma Flow
Paraminohippuric acid (PAH) is freely filtered and
secreted and is almost completely cleared from the renal
plasma
1. amount enter kidney =
RPF x PPAH
~ = amount excreted
2. amount entered
3. ERPF x PPAH
ERPF =
= UPAH x V
~ 10 % PAH
remains
UPAH x V
PPAH
ERPF = Clearance PAH
11
To calculate actual RPF , one must correct
for incomplete extraction of PAH
APAH =1.0
EPAH =
APAH - VPAH
APAH
= 1.0 – 0.1 = 0.9
1.0
normally, EPAH = 0.9
VPAH = 0.1
i.e PAH is 90 % extracted
RPF =
ERPF
EPAH
12
Calculation of Tubular Reabsorption
Reabsorption = Filtration -Excretion
Filt s = GFR x Ps
Excret s = Us x V
13
Calculation of Tubular Secretion
Secretion = Excretion - Filtration
Filt s = GFR x Ps
VPAH = 0.1
Excret s = Us x V
14
Use of Clearance to Estimate Renal
Plasma Flow
Theoretically, if a substance is completely cleared from
the plasma, its clearance rate would equal renal plasma flow
Cx = renal plasma flow
15
Clearances of Different Substances
Substance
Clearance (ml/min
inulin
125
PAH
600
glucose
0
sodium
0.9
urea
70
Clearance of inulin (Cin) = GFR
if Cx < Cin : indicates reabsorption of x
if Cx > Cin : indicates secretion of x
Clearance creatinine (Ccreat) ~ 140 (used to estimate GFR)
Clearance of PAH (CPAH) ~ effective renal plasma flow
16
Effect of reducing GFR
by 50 % on serum
creatinine
concentration and
creatinine excretion
rate
17
Plasma creatinine
can be used to
estimate changes
in GFR
18
Example: Given the following data, calculate the rate
of Na+ filtration, excretion, reabsorption, and secretion
GFR =100 ml/min (0.1 L/min)
PNa = 140 mEq/L
urine flow = 1 ml/min (.001 L/min)
urine Na conc = 100 mEq/L
Filtration Na = GFR x PNa
= 0.1 L/min x 140 mEq/L = 14 mEq/min
Excretion Na = Urine flow rate x Urine Na conc
=.001 L/min x 100 mEq/L
= 0.1 mEq/min
19
Example: Given the following data, calculate the rate
of Na+ filtration, excretion, reabsorption, and secretion
GFR =100 ml/min;
PNa = 140 mEq/L
urine flow = 1 ml/min;
urine Na conc = 100 mEq/L
Filtration Na = 0.1 L/min x 140 mEq/L = 14 mEq/min
Excretion Na = .001 L/min x 100 mEq/L = 0.1 mEq/min
Reabsorption Na = Filtration Na - Excretion Na
Reabs Na = 14.0 - 0.1 = 13.9 mEq/min
Secretion Na = There is no net secretion of Na since
Excret Na < Filt Na
20
Reabsorption of Water and Solutes
21
Primary Active Transport of Na+
22
Mechanisms of
secondary active
transport.
23
Glucose
Transport
Maximum
24
Transport Maximum
Some substances have a maximum rate of tubular transport
due to saturation of carriers, limited ATP, etc
• Transport Maximum: Once the transport maximum is
reached for all nephrons, further increases in tubular
load are not reabsorbed and are excreted.
• Threshold is the tubular load at which transport maximum is
exceeded in some nephrons. This is not exactly the same
as the transport maximum of the whole kidney because
some nephrons have lower transport max’s than others.
• Examples: glucose, amino acids, phosphate, sulphate
25
A uninephrectomized patient with uncontrolled diabetes has a GFR
of 90 ml/min, a plasma glucose of 200 mg% (2mg/ml), and a
transport max (Tm) shown in the figure. What is the glucose
excretion for this patient?
250
200
Glucose
(mg/min)
1. 0 mg/min
2. 30 mg/min
3. 60 mg/min
4. 90 mg/min
5. 120 mg/min
Transport
Maximum
(150 mg/min)
150
Reabsorbed
100
Excreted
.
50
Threshold
0
50 100 150 200 250 300 350
Filtered Load of Glucose
(mg/min)
26
Answer: Filt Glu = (GFR x PGlu) = (90 x 2) = 180 mg/min
Reabs Glu = Tmax = 150 mg/min
Excret Glu = 30 mg/min
250
GFR = 90 ml/min
PGlu = 2 mg/ml
Tmax = 150 mg/min
(mg/min)
200
Glucose
a. 0 mg/min
b. 30 mg/min
c. 60 mg/min
d. 90 mg/min
e. 120 mg/min
Transport
Maximum
(150 mg/min)
150
Reabsorbed
100
Excreted
.
50
Threshold
0
50 100 150 200 250 300 350
Filtered Load of Glucose
(mg/min)
27
Reasorption of Water and Solutes is
Coupled to Na+ Reabsorption
Tubular
Cells
Interstitial
Fluid
- 70 mV
Tubular
Lumen
H+
Na +
glucose, amino
acids
+
Na
3 Na +
2 K+
ATP
Urea
3Na +
H20
ATP
0 mv
2K+
Na +
- 3 mV
Cl- 3 mV
28
Mechanisms by which water, chloride, and urea
reabsorption are coupled with sodium reabsorption
29
Transport characteristics of proximal
tubule.
30
Changes in concentration in proximal
tubule
31
32
Transport characteristics of thin and
thick loop of Henle.
• very permeable to H2O)
~ 25% of filtered load
• Reabsorption of
Na+, Cl-, K+, HCO3-,
Ca++, Mg++
• Secretion of H+
• not permeable to H2O
33
Sodium chloride
and potassium
transport in thick
ascending loop
of Henle
34
Early Distal Tubule
35
Early Distal Tubule
• Functionally similar to thick ascending loop
• Not permeable to water (called diluting segment)
• Active reabsorption of Na+, Cl-, K+, Mg++
• Contains macula densa
36
Early and Late Distal Tubules and
Collecting Tubules.
~ 5% of filtered load
NaCl reabsorbed
• not permeable
to H2O
• not very
permeable to
urea
• permeablility
to H2O depends
on ADH
• not very
permeable to
37
urea
Late Distal and Cortical Collecting
Tubules Principal Cells – Secrete K+
38
Late Distal and Cortical Collecting
Tubules Intercalated Cells –Secrete H+
Tubular Cells
Tubular Lumen
H2O (depends on
ADH)
K+
H+
K+
ATP
ATP
Na +
K+
H+
ATP
ATP
ATP
Cl -
39
Transport characteristics of medullary
collecting ducts
40
Normal Renal Tubular Na+ Reabsorption
5-7 %
(16,614 mEq/day)
25,560
mEq/d
(1789 mEq/d)
65 %
25 %
(6390
2.4%
mEq/d)
(617 mEq/day)
0.6 %
(150 mEq/day)
41
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)
42
Changes in
concentrations
of substances
in the
renal tubules
43
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 waterhas been reabsorbed up to that point?
A = 1/3 (33.33 %) remains
66.67 % reabsorbed
3.0
A
8.0
B
B = 1/8 (12.5 %) remains
87.5 % reabsorbed
C = 1/50 (2.0 %) remains
98.0 % reabsorbed
C 50
44
Regulation of Tubular Reabsorption
• Glomerulotubular Balance
• Peritubular Physical Forces
• Hormones
- aldosterone
- angiotensin II
- antidiuretic hormone (ADH)
- natriuretic hormones (ANF)
- parathyroid hormone
• Sympathetic Nervous System
• Arterial Pressure (pressure natriuresis)
• Osmotic factors
45
Glomerulotubular Balance
Tubular
Reabsorption
Tubular Load
46
Importance of Glomerulotubular Balance
in Minimizing Changes in Urine Volume
GFR
125
150
Reabsorption
Urine Volume
% Reabsorption
no glomerulotubular balance
124
1.0
124
26.0
99.2
82.7
“perfect” glomerulotubular balance
150
148.8
1.2
99.2
47
Peritubular capillary reabsorption
48
Peritubular Capillary Reabsorption
Reabs = Net Reabs Pressure (NRP) x Kf
= (10 mmHg) x (12.4 ml/min/mmHg)
Reabs = 124 ml/min
49
Determinants of Peritubular
Capillary Reabsorption
Kf
Reabsorption
Pc
Reabsorption
c
Reabsorption
50
Determinants of Peritubular
Capillary Hydrostatic Pressure
Glomerular
Capillary
Ra
Re
Peritubular
Capillary (Pc)
Arterial
Pressure
Pc
Arterial Pressure
Reabs.
Ra
Pc
Reabs.
Re
Pc
Reabs.
51
Determinants of Peritubular Capillary
Colloid OsmoticPressure
c
Reabsorption
Plasm. Prot.
Filt. Fract.
a
c
c
Filt. Fract. = GFR / RPF
52
Factors That Can Influence
Peritubular Capillary Reabsorption
Kf
Pc
Ra
Re
Art. Press
c
a
Filt. Fract.
Reabsorption
Reabsorption
Pc ( Reabs)
Pc ( Reabs)
Pc ( Reabs)
Reabsorption
c
c
53
Effect of increased
hydrostatic pressure
or decreased colloid
osmotic pressure
in peritubular
capillaries to reduce
reabsorption
54
Question
Which of the following changes would tend to
increase peritubular reabsorption ?
1. increased arterial pressure
2. decreased afferent arteriolar resistance
3. increased efferent arteriolar resistance
4. decreased peritubular capillary Kf
5. decreased filtration fraction
55
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
56
Late Distal, Cortical and Medullary
Collecting Tubules
Principal Cells
Tubular Lumen
H20 (+ ADH)
Na
K+
Na +
+
ATP
ATP
K+
Cl -
Aldosterone
57
Abnormal Aldosterone Production
• Excess aldosterone (Primary aldosteronism
Conn’s syndrome) - Na+ retention,
hypokalemia, alkalosis, hypertension
• Aldosterone deficiency - Addison’s disease
Na+ wasting, hyperkalemia, hypotension
58
Control of Aldosterone Secretion
Factors that increase aldosterone secretion
• Angiotensin II
• Increased K+
• adrenocorticotrophic hormone (ACTH)
(permissive role)
Factors that decrease aldosterone secretion
• Atrial natriuretic factor (ANF)
• Increased Na+ concentration (osmolality)
59
Angiotensin II Increases Na+ and Water
Reabsorption
• Stimulates aldosterone secretion
• Directly increases Na+ reabsorption
(proximal, loop, distal, collecting tubules)
• Constricts efferent arterioles
- decreases peritubular capillary
hydrostatic pressure
- increases filtration fraction, which increases
peritubular colloid osmotic pressure)
60
Angiotensin II increases renal
tubular sodium reabsorption
61
Effect of Angiotensin II on Peritubular
Capillary Dynamics
Glomerular
Capillary
Ra
Peritubular
Capillary
Re
Arterial
Pressure
Ang II
Re
Pc (peritubular cap. press.)
renal blood flow
FF
c
62
Ang II constriction of efferent arterioles causes Na+ and
water retention and maintains excretion of waste
products
Na+ depletion
Ang II
Resistance efferent arterioles
Glom. cap. press
Prevents decrease
in GFR and
retention of
waste products
Renal blood flow
Peritub. Cap. Press.
Filt. Fraction
Na+ and H2O Reabs.
63
Angiotensin II blockade decreases Na+
reabsorption and blood pressure
• ACE inhibitors (captopril, benazipril, ramipril)
• Ang II antagonists (losartan, candesartin, irbesartan)
• Renin inhibitors (aliskirin)
• decrease aldosterone
• directly inhibit Na+ reabsorption
• decrease efferent arteriolar resistance
Natriuresis and Diuresis +
Blood Pressure
64
Antidiuretic Hormone (ADH)
• Secreted by posterior pituitary
• Increases H2O permeability and reabsorption in
distal and collecting tubules
• Allows differential control of H2O and solute
excretion
• Important controller of extracellular fluid
osmolarity
65
ADH synthesis in
the magnocellular
neurons of
hypothalamus,
release by the posterior
pituitary, and action
on the kidneys
66
Mechanism of action of ADH in distal
and collecting tubules
67
Feedback Control of Extracellular Fluid
Osmolarity by ADH
Extracell. Osm
(osmoreceptorshypothalamus
ADH secretion
(posterior pituitary)
Tubular H2O permeability
(distal, collecting)
H2O Reabsorption
(distal, collecting)
H2O Excretion
Abnormalities of ADH
• Inappropriate ADH syndrome (excess ADH)
- decreased plasma osmolarity, hyponatremia
• “Central” Diabetes insipidus (insufficient ADH)
- increased plasma osmolarity, hypernatremia,
excess thirst
69
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
70
Atrial Natriuretic Peptide (ANP)
Blood volume
ANP
Renin release
aldosterone
GFR
Ang II
Renal Na+ and H2O reabsorption
Na+ and H2O excretion
71
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++
72
Control of Ca++ by Parathyroid Hormone
Extracellular
[Ca++]
Vitamin D3
Activation
Ca++
Intestinal
Reabsorption
PTH
Renal Ca++
Reabsorption
Ca++ Release
From Bones
73
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)
74
Increased Arterial Pressure Decreases Na+
Reabsorption (Pressure Natriuresis)
• Increased peritubular capillary hydrostatic
pressure
• Decreased renin and aldosterone
• Increased release of intrarenal natriuretic factors
- prostaglandins
- EDRF
75
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)
76
Abnormal Tubular Function :
Increased Reabsorption
• Conn’s Syndrome: primary aldosterone excess
• Glucocorticoid Remediable Aldosteronism (GRA):
excess aldosterone secretion due to abnormal
control of aldosterone synthase by ACTH
(genetic)
• Renin secreting tumor: excess Ang II formation
• Inappropriate ADH syndrome: excess ADH
• Liddle’s Syndrome: excess activity of amiloride
sensitive Na+ channel (genetic)
77
“Escape” from Sodium Retention
During Excess Aldosterone Infusion
Mean
Arterial
Pressure
(mmHg)
Urinary
sodium
Excretion
(x normal)
Aldosterone Infusion
130
100
1
0
2
Time (days)
4
6
78
• Conn’s
-
syndrome: (primary aldosteronism)
Na+ reabsorption (distal & coll. tub.)
Na+ excretion (in steady-state)
K+ secretion (transient)
K+ excretion (in steady-state)
plasma K+
blood pressure
plasma renin
79
Abnormal Tubular Function:
Renin secreting tumor : (increased
angiotensin II + increased aldosterone)
Na+ reabsorption (distal & coll. tub.)
Na+ excretion (in steady-state)
K+ secretion (transient)
K+ excretion (in steady-state)
plasma K+
- blood pressure
aldosterone
80
Abnormal Tubular Function:
• Inappropriate ADH syndrome:
-
water reabsorption
water excretion (urine volume)
plasma Na+
81
Liddle’s Syndrome: Excess Activity of Amiloride
Sensitive Na+ Channel in Late Distal and Cortical
Collecting Tubules
Tubular Lumen
Tubular Cells
H20
K+
Na +
K+
Na +
ATP
ATP
Cl -
Treatment
Na+ channel blockers:
- Amiloride
- Triamterene
82
Abnormal Tubular Function:
Liddle’s syndrome: (excess Na+ channel
activity in late distal and collecting)
Na+ reabsorption (distal & coll. tub.)
Na+ excretion (in steady-state)
blood pressure
plasma renin
aldosterone
83
Assessing Kidney Function
• Plasma concentration of waste products
(e.g. BUN, creatinine)
• Urine specific gravity, urine concentrating ability;
• Urinalysis test reagent strips (protein, glucose, etc)
• Biopsy
• Albumin excretion (microalbuminuria)
• Isotope renal scans
• Imaging methods (e.g. MRI, PET, arteriograms,
iv pyelography, ultrasound etc)
• Clearance methods (e.g. 24-hr creatinine clearance)
• etc
84
85