RENAL CLEARANCE(CONTD)
How Creatinine Clearance is used in estimation of GFR
Application of Clearance in the measurement of renal plasma flow
Inulin Clearance as an Estimate
of GFR
• INULIN
• - polysaccharide that is freely filtered at the
glomerulus but is neither reabsorbed or
secreted
• - rate of filtration = rate of excretion
( GFR x PIN ) =
GFR =
( UIN x V )
UIN x V
PIN
• Other substances used to estimate GFR:
• 1. radioactive iothalamate
• 2. mannitol
• 3. creatinine
- endogenous product of muscle
metabolism
- present in plasma at a fairly constant
concentration
- small amount is secreted by the
tubules
- amount excreted > amount filtered
• Comparison of inulin clearance with
clearance of other substances:
• 1. If clearance rate of a substance is equal to
inulin clearance
substance is filtered but
not reabsorb or secreted
• 2. If clearance rate of a substance is less
than inulin clearance substance is
reabsorbed
• 3. If clearance rate of a substance is greater
than inulin clearance
substance is
secreted
•
Substance
(ml/min)
• glucose
• sodium
• chloride
• potassium
• phosphate
• inulin
• creatinine
Clearance rate
0
0.9
1.3
12.0
25.0
125.0
140.0
• If one knows the rate of filtration (GFR x PS)
and the rate of renal excretion (US x V):
•
(GFR x PS) > (US x V)
reabsorption
•
(GFR x PS) < (US x V)
secretion
Para-aminohippurate (PAH)
Clearance as a measure of
Plasma Flow
• PAH
• - substance that is completely cleared from plasma
by both filtration and secretion
• - freely filterable at the glomerulus and most of the
PAH remaining in plasma after filtration is
secreted from the peritubular capillaries into the
proximal convoluted tubule
• - PAH is almost completely cleared from the plasma
entering the kidneys
Amount of PAH
entering the kidney
=
Amount of PAH
excreted in urine
Renal Plasma Flow x PPAH = UPAH x V
Effective Renal Plasma Flow =
UPAH x V
PPAH
- 10-15% of plasma entering the kidney (TRPF)
supplies the non-filtering and non-secreting areas
of the kidneys (eg. peripelvic fat)
-Effective Renal Plasma Flow (ERPF) is only
85-90% of Total Renal Plasma Flow (TRPF)
Extraction ratio of PAH:
- amount of PAH removed from the blood
- about 90%
- equals to: PPAH – VPAH
PPAH
PPAH = renal arterial PAH
VPAH= renal venous PAH
PAH clearance
Total Renal Plasma Flow (TRPF) =
Extraction ratio
Total Renal Blood Flow (TRBF) =
ERPF
1 – Hematocrit
Filtration Fraction (FF) =
GFR
RPF
URINARY CONCENTRATION
AND DILUTION
2 Basic Requirements For The
Formation of a Concentrated
Urine
• 1. High levels of ADH
• - increases the permeability of the distal
tubules and collecting ducts to water
• 2. High osmolality of the renal medullary
interstitial fluid
•
- provides the osmotic gradient
necessary
for water reabsorption to occur in the
presence of high levels of ADH
ANTIDIURETIC HORMONE
(ADH, Vasopressin)
• peptide hormone synthesized in the hypothalamus and stored
in the posterior pituitary
• determines the water permeability of the late distal tubules
and the collecting ducts:
•
 ADH
 water permeability
•
 ADH
 water permeability
• also increase the permeability of the inner medullary
collecting ducts and papillary ducts to urea
• mechanism of action:
• - ADH binds to receptors on the basal-lateral
surfaces of epithelial cells………..activate adenylate
cyclase………increase cAMP…….insertion of protein
channels for water in the luminal membrane
• operates by altering renal excretion of water without affecting
the rate of solute excretion
• determines whether the kidney will excrete a dilute or a
concentrated urine:
•  ADH………. reabsorption of water in collecting
duct………. urine volume……..concentrated urine
•  ADH…….. reabsorption of water in collecting
duct…….. urine volume…….dilute urine
• REGULATION OF ADH SECRETION
• Increase ADH
Decrease ADH
•  plasma osmolality
 plasma osmolality
•  blood volume
 blood volume
•  blood pressure
 blood pressure
• nausea
drugs:
• hypoxia
alcohol
• drugs:
clonidine
•
morphine
•
nicotine
•
cyclophosphamide
haloperidol
COUNTERCURRENT MECHANISMS
• process by which the medullary interstitial fluid
becomes hyperosmotic
• depends on the specialized anatomical arrangement
of the loops of Henle and the vasa recta (specialized
peritubular capillaries in the renal medulla
Major factors that contribute to the
buildup of solute concentration in the
renal medulla
• 1. Active transport of sodium and co-transport of
potassium, chloride and other ions out of the thick
ascending limb into the medullary interstitium
• 2. Active transport of ions from the collecting ducts
into the medullary interstitium
• 3. Passive diffusion of large amounts of urea from
the inner medullary collecting ducts into the
medullary interstitium
• 4. Diffusion of water from the medullary tubules
into the medullary interstitium is far less than the
reabsorption of solutes
Countercurrent Multiplier
System
• involves the loop of Henle
• the process which establishes or produce the high osmolality
of the renal medulla
• can raise the interstitial fluid osmolality in the medulla to
1200-1400 mOsm/L
• the most important cause of the high medullary osmolality is
the active transport of sodium and co-transport of potassium,
chloride and other ions from the thick ascending limb of
Henle’s loop in to the medullary interstitium
Countercurrent
Exchange Mechanism
• involves the vasa recta
• responsible for the preservation of the hyperosmolality of the
renal medulla
• Two special features of the renal medullary blood flow that
contribute to the preservation of the high solute concentration:
• 1. The medullary blood flow is low
• 2. The vasa recta serves as a countercurrent
exchanger which minimize the washout of solutes
from the medullary interstitium
Countercurrent mecanism and concentration of
urine
Urea Recirculation
• refer to illustration
• urea contributes about 40% of the osmolality of the renal medullary
interstitum
• provides an additional mechanism for the formation of a
hyperosmotic renal medulla
Formation of a Dilute Urine
• fluid leaving the ascending loop of Henle and early
distal tubule is always dilute , regardless of the level
of ADH
• the mechanism for the formation of a dilute urine
is the continued reabsorption of solutes from the
distal segments of the tubular system with little or
no reabsorption of water in the absence of ADH
• results in the excretion of a large volume of dilute
urine
Formation of a Concentrated
Urine
• concentrated urine is formed by the continued excretion of
solutes by the tubules while water reabsorption is increased
in the presence of ADH
• results in the excretion of a small volume of concentrated
urine
• Obligatory Urine Volume:
• - minimum volume of urine that must be excreted
per day to remove the 600 mOsm of solute wastes
produced by the body per day
• - would equals 500 ml (0.5 L) if the maximal
concentrating ability of the kidney is about 1200
mOsm/day
REGULATION OF
VOLUME AND
OSMOLARITY OF
BODY FLUIDS
• dependent almost exclusively on the
regulation of water and sodium balance
I. CONTROL OF WATER BALANCE
• A. THIRST - control water input
• B. ADH
- control water
output
A. Thirst
• conscious desire to drink
• thirst center in the CNS: Hypothalamus
- anteroventral region of the third ventricle
(AV3V)
- preoptic nuclei
• threshold for drinking: increase in sodium
concentration of about 2 meq/L above normal
• CONTROL OF THIRST
• Increase Thirst
•  osmolality
•  blood volume
•  blood pressure
•  angiotensin II
• dryness of the mouth
Decrease Thirst
 osmolality
 blood volume
 blood pressure
 angiotensin II
gastric distension
B. Antidiuretic Hormone (ADH)
• increase the water permeability of the collecting duct
cell (principal cell)
• increase water reabsorption
• decrease water excretion
• synthesized in the hypothalamus: 5/6 in the supraoptic
nuclei and 1/6 in the paraventricular nuclei
• stored and released from the posterior pituitary
Control of ADH Secretion
• 1. BARORECEPTOR CONTROL
• 1.1 Arterial Baroreceptor Reflex
•
•
•
1.2 Cardiopulmonary Baroreceptor Reflex
- found in the atria and in the veins
- detects changes in arterial pressure and blood
volume……afferent impulses carried by vagus
and glossopharyngeal nerves…….nucleus tractus
solitaries…….hypothalamus
Control of ADH Secretion Contd
• 2. OSMORECEPTOR CONTROL
• Osmoreceptor cells
•
- special nerve cells in the hypothalamus that are
stimulated by an increase in plasma osmolality
•
- stimulation is brought about by shrinkage of
these cells in the presence of high plasma
osmolality……..supraoptic nuclei…….posterior
pituitary……..increased ADH secretion
Control of ADH Secretion Contd
• under normal condition, thirst and ADH secretion are primarily under the control of
osmoreceptors due to the extreme sensitivity of osmoreceptors to small changes in plasma
osmolality
• during severe intravascular volume depletion, thirst and ADH secretion will be primarily affected
by the baroreceptors
“ volume overides tonicity”
 Plasma volume
 Firing of
baroreceptors
Nucleus tractus
solitarius
Hypothalamus
 Plasma osmolality
Stimulation of
osmoreceptors
 ADH secretion
 Collecting duct
permeability to water
 Water reabsorption
 Water excretion
 Thirst
 Water intake
 Plasma
volume