Adelina Vlad, MD PhD
Urine formation resultsfrom:
Glomerular filtration
Tubular reabsorption
Tubular secretion
Excretion = Filtration Reabsorbtion + Secretion
Reabsorption and Secretion by the Renal Tubules
Tubular Reabsorption
Is a highly selective process
By controlling the reabsorbtion rate, the kidney adjust the
excretion of specific compounds
Reabsorption by the Renal Tubules
Amount filtered = Glomerular ltration rate x Plasma concentration
Reabsorbtion and Secretion Mechanisms
Active Transport Against an electrochemical gradient
With energy consumption (ATP)
Primary active transport
Directly connected to an energy source (Na/K-ATPase, Na/H-ATPase, H-ATPase, Ca-ATPase)
E.g.: Na+ reabsorbtion
Na/K pump in the laterobasal membrane creates an
electrochemical gradient favouring Na+ facilitated diffusion from
the tubular lumen
At the apical site: passive reabsorbtion through cotransporters
and exchangers (PT, TAL, DCT) or epithelial Na+ channels
(ENaC, in the collecting ducts)
Secondary active transport
Two or more substances interact with a carrier molecule
The energy liberated from the downhill movement of one of the
substances enables uphill
movement of a second substance
Co-transport: same direction(reabsorbtion of glucose,
aminoacids in the proximal tubule,
and Na+/K+/Cl- in the TAL and
DCT)
Counter-transport: opposite direction (secretion of H+ in the
proximal tubule)
Pynocitosis
Active transport mechanism
Characteristic to reabsorbtion of large molecules (proteins)
Proteins are incorporated in pynocitosis vesicles at the luminal
side of the tubular cell; inside the vesicles, the proteins are
digested to aminoacids that passively diffuse into the interstitial
fluid and further into the peritubular capillaries
Transport Maximum= The limit to the rate at which a
substance can be transported
- Is characteristic to active
transport
- Appears when the transport
system gets saturated
Saturation - the tubular load
exceeds the capacity of the
carrier/enzyme
Threshold the filtered load of substance (glucose) at which the
substance (fully reabsorbed, not
secreted) begins to be excreted
in the urine
Substances actively reabsorbed
Substances actively secreted
Substances Passively Reabsorbed
Do not demonstrate a transport maximum
Their rate of transport is determined by:
the electrochemical gradient for diffusion
the permeability of the membrane
the time that the fluid containing the substance remains within the
tubule
Transport of this type is referred to as gradient-time transport
Water Reabsorbtion
Transcellular and paracellular
Depends on the permeability of each tubule segment
High in the proximal tubule
Low in the other segments; ADH-dependent in late distal and
collecting tubules
Realised by osmosis
Follows Na+ reabsorbtion
Contributes to the reabsorbtion of other solutes through solvent
drag
Paracellular transport of Na+, passive
Governed by the transepithelial electrochemical gradient for Na+
Proximal tubule and thick ascending limb of the loop of Henle:
Na+ reabsorbtion
The other tubule segments: backleak of Na+
The leakiness of the paracellular pathway decreases along the nephron from the proximal tubule (the most leaky) to the papillary
collecting ducts
Chloride reabsorbtion
Paracellular pathway (PT, CD), by the electrochemical gradient
Transcellular pathway, involving K+/Cl- cotransporter (PT, DCT),
Na+/Cl- cotransporter (DCT), Na+/K+/Cl- cotransporter (TAL) and
HCO3-/Cl- exchanger (CD) across the apical site, and Cl-
channels at the basolateral membrane
Urea reabsorbtion and secretion
PT: solvent drag, facilitated diffusion (paracellular and
transcellular reabsorbtion)
Thin LH: ureea secretion through urea transporter UT2
CD: ureea reabsorbtion mediated by UT1 and UT4
Water, chloride, and urea reabsorbtion is coupled with
sodium reabsorbtion
Reabsorption and SecretionAlong Different Parts of
the Nephron
Proximal Tubule Reabsorbtion
very active
PT is highly permeable to water
glucose, AA reabs. in the first half
Na+: cotransport with AA, glucose,
exchanger with H+
Cl- (terminal part), HCO3-, K+, urea
HCO3- reabsorbtion depends on
carbonic anhidrase activity
Secretion
H+, bile salts, oxalate, urate,
catecholamines
toxins, drugs (penicillin,
salicylates, PAH)
The Loop of Henle
Thick ascending loop of Henle
The Descending Loop
highly permeable to water (approx. 20% of the filtered water is
reabsorbed here)
moderately permeable to most solutes (urea, sodium)
The Ascending Loop
Impermeable to water and
urea
The thick segment:
reabsorption of sodium,
chloride, potassium
(25% of the filtered
amount), calcium,
bicarbonate,
magnesium
the filtrate becomes hypotonic
secretion of hydrogen
ions
Thick
ascending
segment
5%
Distal and Cortical Collecting Tubules Early DT
Impermeable to water and urea
Reabsorbs sodium, potassium, chloride
diluting segment
Principal cell
Late DT and Cortical CT
Impermeable to urea
ADH-dependent water permeability
Principal Cells
Na+ reabsorbtion,
K+ secretion (Na/K-ATPase
pump), controlled by aldosterone
Intercalated Cells
H+ secretion by a hydrogen-
ATPase pump, against a large
concentration gradient (1000 to 1)
for each H+ secreted, a HCO3 is reabsorbed
reabsorbtion of K+
Medullary Collecting Duct
Reabsorbtion of 10% of the filtered water (ADH - dependent)
and Na+, important in determining
the final urine output of water and
solutes
Reabsorption of urea into the medullary interstitium, helps to
raise the osmolality in this region,
important for the urine
concentration process
Secretion of H+ against a largeconcentration gradient, as in the
cortical collecting tubule
Regulation of Tubular Reabsorption
Glomerulotubular Balance
= The tubules adjust the reabsorption rate according to the
tubular load
Realised by changes in physical forces in the tubule and
surrounding renal interstitium
Can be demonstrated in completely isolated kidneys
Helps prevent overloading of the distal tubular segments
when GFR increases
Peritubular Capillary Physical Forces
Reabsorption = Kf x Net reabsorptive force
Peritubular capillary reabsorbtion depends on two factors directly influenced by renal hemodynamic changes:
The hydrostatic pressure in the peritubular capillaries, Pc:
influenced by the arteryal pressure and the afferent and
efferent arterioles resistance
The colloid osmotic pressure in the peritubular capillaries, pc:
determined by the systemic plasma colloid osmotic pressure
and the filtration fraction
Renal Interstitial Hydrostatic and Colloid Osmotic Pressures
Changes in peritubular capillary physical forces changes of the physical forces in the renal interstitium surrounding the tubules influence tubular reabsorption:
Forces that increase peritubular capillary reabsorption increase
reabsorption from the renal tubules
Hemodynamic changes that inhibit peritubular capillary
reabsorption inhibit tubular reabsorption of water and solutes
Humoral and Nervous Influences on Tubular Reabsorbtion and Secretion
Angiotensin II
Stimulates aldosterone secretion, which in turn increases
sodium reabsorption
Constricts the efferent arterioles raises filtration fraction inthe glomerulus
increased colloid osmotic pressure in the peritubularcapillaries, with consecutive raise of tubular reabsorption of
sodium and water
Directly stimulates sodium reabsorption in the proximal
tubules, the loops of Henle, the distal tubules, and the
collecting tubules
Sympathetic Nervous System Activation
Decreases sodium excretion by
Increasing sodium reabsorbtion in the proximal tubule and the
ascending limb of the loop of Henle
Incresing the renin release
Constricting afferent and efferent arterioles
Use of Clearance Methods to Quantify Kidney FunctionThe renal clearance of a substance is the volume of plasma that is
completely cleared of that substance by the kidneys per unit time
The clearence of
inulin and
creatinine can be
used to estimate
the GFR:
PAH clearence can be used to estimate the Renal Blood
Flow:
PAH para-aminohippuric acid
Urine Concentration and Dilution
Urine Concentration and Dilution
The body water is controlled by:
Fluid intake, which is regulated by factors that determine thirst
Renal excretion of water, controlled by factors that influence
glomerular filtration and tubular reabsorption
The renal ability to preserve the hydro-electrolitic homeostasis is based on:
The mechanisms that cause the kidneys to eliminate excess
water by excreting a dilute urine
The mechanisms that cause the kidneys to conserve water by
excreting a concentrated urine
The renal feedback mechanisms that control the extracellular
fluid sodium concentration and osmolarity
Formation of a Dilute Urine
When there is a large excess of water in the body, the kidney can excrete as much as 20 L/day of dilute urine, with a concentration as
low as 50 mOsm/L
How?
By continuing to reabsorb solutes while failing to reabsorb water in
the distal parts of the nephron, where water reabsorbtion is ADH-
dependent (late distal tubule and the collecting ducts)
Proximal tubule: Tubular fluid remains isosmotic
Descending loop of Henle: Water is reabsorbed by osmosis untilthe tubular fluid reaches equilibrium with the interstitial fluid of the
renal medulla, which is very hypertonic
Ascending loop of Henle: Tubular fluid becomes dilute (100 mOsm/L) by the time the fluid enters the early distal tubular segment
- regardless of whether ADH is present or absent
Distal and collecting tubules: Tubular fluid in is further diluted (50 mOsm/L) in the absence of ADH; the failure to reabsorb water
and the continued reabsorption of solutes lead to a large volume
of dilute urine
When there is a water deficit in the body, the kidney forms a concentrated urine
How?
By continuing to excrete solutes while increasing water
reabsorption and decreasing the volume of urine formed
Formation of a Concentrated Urine
Obligatory Urine Volume
= The minimal volume of urine that must be excreted in order to eliminate the solutes in excess from the body
Depends on:
the average amount of solutes that must be eliminated:
about 600 mOsm of solute/day for a healthy 70-kg human
the maximal urine concentration capacity of the kidney:
1200 mOsm/L to 1400 mOsm/L
Obligatory urine volume:
The minimal loss of volume in the urine contributes todehydration, along with water loss from the skin, respiratory tract,
and gastrointestinal tract, when water is not available to drink
The basic requirements for forming a concentrated urine are:
A high level of ADH, which increases the permeability of the
distal tubules and collecting ducts to 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
Formation of a Concentrated Urine
The osmolarity of interstitial fluid in almost all parts of the body is about 300 mOsm/L
The osmolarity of the interstitial fluid in the medulla of the kidney is
increasing progressively to about 1200 to 1400 mOsm/L towards the
papilla
How?
The renal medullary interstitium accumulates solutes in great excess
of water
The Countercurrent Mechanism
Responsible for making the renal medullary interstitial uidhyperosmotic
Depends on:
The special anatomical arrangement of the loops of Henle (LH)
25% of the nephrons are juxtamedullary, with long LH
descending deep into the renal medulla
The special anatomical arrangement of vasa recta
They parallel the LH of juxtamedullary nephrons
The collecting ducts which carry urine through the hyperosmoticrenal medulla also play a role in the countercurrent mechanism
Major factors that contribute to the buildup of solute concentration
into the renal medulla:
Active transport of sodium ions and co-transport of potassium,chloride, and other ions out of the thick portion of the ascending
limb of the loop of Henle into the medullary interstitium
Active transport of ions from the collecting ducts into the medullaryinterstitium
Facilitated diffusion of large amounts of urea from the inner medullary collecting ducts into the medullary interstitium
Diffusion of only small amounts of water from the medullary tubules into the medullary interstitium, far less than the reabsorption of
solutes into the medullary interstitium
The characteristics of the loop of Henle cause solutes to be trapped
in the renal medulla:
Sodium, potassium, chloride, and other ions are transported from TAL into the interstitium; the concentration gradient created between
the lumen and the interstitium cannot exceed 200 mOsm
TAL is impermeable to water solutes are added in excess to water to the renal medullary interstitium
Sodium chloride is passively reabsorbed from the thAL, impermeable to water as well solutes are added further to the high solute concentration of the renal medullary interstitium
The descending limb of Henles loop is permeable to water the tubular uid osmolarity gradually rises as it ows toward the tip of the loop of Henle
The repetitive reabsorption of sodium chloride from the thick ascending loop
of Henle and continuous inflow of new sodium chloride from the proximal
tubule into the loop of Henle is called the countercurrent multiplier
Steps Involved in Causing Hyperosmotic Renal Medullary Interstitium
Role of Distal Tubule and CollectingDucts In the presence of high concentration of ADH, the late distal tube and
cortical collecting tubule become highly permeable to water
The water from the cortex interstitium is swept away by the rapidly flowing peritubular capillaries
The collecting ducts become permeable to water as well in the presence of high levels of ADH the fluid at the end of the collecting ducts has the same osmolarity as the interstitial fluid of the
renal medulla - about 1200 mOsm/L
The water is removed from the medullary interstitium through vasa recta
Urea Contributes to HyperosmoticRenal Medullary Interstitium Urea contribution = 40 50 % (500 - 600 mOsm/L) when the kidney
is forming a maximally concentrated urine
How?
Along the tubule, the concentration of urea increases:
Proximal Tubule:
Is less permeable for ureea than for water
40 50 % of urea present in the filtrate is reabsorbed, but urea concentration rises due to intense water reabsorbtion
Thin Loop of Henle:
The concentration of urea continues to rise because of
water reabsorption
secretion of urea into the thin loop of Henle from the medullary
interstitium
Thick Loop of Henle, Distal Tubule and Cortical Colecting Tubule:
Impermeable to urea
With high ADH plasma levels, large amounts of water are
reabsorbed urea becomes more concentrated
Inner Medullary Collecting Duct:
More water is reabsorbed, urea concentrates further
The concentration gradient leads to urea diffusion from the IMCD
into the medullar interstitium; this diffusion is facilitated by specific
urea transporters (eg. UT-AI, activated by ADH)
Urea Recirculation A moderate share of the urea that moves into medullary interstitium
diffuses into the thin loop of Henle, passes again through the
ascending LH, DT, CCT, and back down into the MCD
Urea can recirculate several times before it is excreted, contributing to a higher concentration of urea
This mechanism for concentrating urea before it is excreted is essential for keeping water into the body when water is in short
supply
When there is excess water in the body (low ADH), the IMCD permeability for water and urea decreases and more urea is
excreted in the urine
Importance of the Vasa Recta Vasa recta preserve
hyperosmolarity of the renal
medulla because
The blood flow is low: 2 5 % of the total renal blood flow,
sufficient to supply the
metabolic needs of the tissues
and low enough to minimize
solute loss from the medullary
interstitium
They serve as countercurrent
exchangers, minimizing
washout of solutes from the
medullary interstitium
The Vasa Rectas Countercurrent Exchange Mechanism Plasma flowing down the descending limb of the vasa recta
becomes more hyperosmotic because of diffusion of water out of
the blood and diffusion of solutes from the renal interstitial fluid
into the blood
In the ascending limb of the vasa recta, solutes diffuse back into the interstitial fluid and water diffuses back into the vasa recta
Certain vasodilators or large increases in arterial pressure can markedly increase renal medullary blood flow, washing out some of the solutes from the renal medulla and reducing maximum urine
concentrating ability
Changes in osmolarity of the tubular fluid in the presence of high
levels of antidiuretic hormone (ADH) and in the absence of ADH
Osmoreceptor-ADH Feedback System
Cardiovascular Reflex Stimulation of ADH Release In addition to increased osmolarity, two other stimuli increase
ADH secretion:
(1) decreased arterial pressure
(2) decreased blood volume
Afferent stimuli are carried by the vagus and glossopharyngeal nerves from high-pressure regions of the circulation (the aortic
arch and carotid sinus) and low-pressure regions (cardiac atria) up
to the tractus solitarius
Projections from these area stimulate the hypothalamic nuclei that control ADH synthesis and secretion
ADH is more sensitive to small changes in osmolarity than to
similar changes in blood volume:
An increase of plasma osmolarity
of 1% is sufficient to increase ADH
levels
A decrease in blood volume of
more than 10% increases
significantly the ADH levels
The day-to-day regulation of ADH secretion is effected by changes in
plasma osmolarity
With severe decreases in blood
volume, the cardiovascular reflexes
play a major role in stimulating ADH
secretion
Stimuli for ADH Secretion; Thirst Control
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