Structure of Kidney

    Kidney is separated into cortical and medullary regions
    The medulla is further divided into medullary segments called renal or medullary
    The functional unit of the kidney is the nephron. It can be divided up into the
Glomerular Capsule OR Bowmans Capsule. Proximal Convoluted Tubule, Loop of
Henle, Distal Convoluted Tubule and Collecting Duct

     Renal blood flow is approximately 20% of C.O. The vast majority (90%) of this
is filtered in the cortex layer at the Bowmans Capsule

    Structure of Bowmans Capsule that allows for filtration:
    Glomerular capillaries have fenestrations which act as pores for small molecules
to pass through.
    A basement membrane exists past this and prevents large molecules from passing
    Podocytes are specialized cells which sit beyond the Basement membrane and
their „feet‟ provide another level of filtration.

Basic Renal Processes

   The three basic renal processes are glomerular filtration, tubular reabsorption and
    tubular secretion.
    Glomerular Filtration: The filtration of plasma from the glomerular capillaries into
    Bowmans space
    Tubular Reabsorption: The movement of fluid from the tubule lumen (proximal
    tubule, loop of Henle, distal tubule, collecting ducts) to the peritubular capillary
    Tubular secretion: The movement of fluid in the peritubular capillary plasma to the
    tubule lumen.
   As a consequence, the amount of any substance excreted in the urine is equal to
       Amount excreted = amount filtered + amount secreted (– amount reabsorbed)
   The degree to which a compound is reabsorbed or secreted following glomerular
    filtration depends on the nature of the compound and the homeostatic mechanisms to
    control it.
   Most of the tubular reabsorption and secretion occurs in the proximal tubule, the
    Loop of Henle reabsorbs large amounts of ions. The distal tubule act as a „fine
    tuning‟ mechanism and are under neural and hormonal control.

Glomerular Filtration

   The glomerular filtrate is identical to blood plasma except there are no cells and no
    large molecular weight proteins (the albumin‟s and globulin‟s). Compounds that are
    bound to these large proteins (Ca2+ and fatty acids) are also absent from the
    glomerular filtrate.
 The pressures involved in the bulk flow of fluid between capillaries and the ISF also
    exist between the glomerular capillaries and the Bowmans Space. These are as
    The glomerular capillary hydrostatic pressure (PGC)  60 mmHg
    Bowmans space hydrostatic pressure (PBS)  15 mmHg
    The osmotic pressure of the glomerular capillary plasma (GC)  29 mmHg
NOTE: These forces are identical to the Starling forces that exist between the capillaries
and ISF. The magnitude of GC is larger than ISF.
 The net glomerular filtration pressure is a function of the above forces
                     Net glomerular filtration pressure = PGC  PBS   GC
As a result of the above forces there is a NETglomerular filtration pressure of 16 mmHg
forcing fluid out of the glomerular capillary and into Bowmans space
 The volume of fluid filtered per unit time across the glomerular capillary is called the
    Glomerular Filtration Rate (GFR)
 GFR is related to filtration pressure, glomerular capillary permeability and glomerular
    capillary surface area.
 GFR is normally 180 litres per day. Recall that plasma volume is 3 litres. As a
    consequence the blood plasma is filtered 60 times a day through the kidneys
 GFR can be regulated by neural and hormonal input to the afferent and efferent
    arterioles thus changing glomerular filtration pressure.

Regulation of GFR

GFR is kept relatively constant under most conditions through three mechanisms. First
two of which are intrinsic to the kidneys themselves (Renal Autoregulation)
   1. Myogenic response of the smooth muscle in the afferent arterioles. Changes in
       blood pressure induce contraction or dilation of smooth muscle in afferent
       arterioles to keep GFR constant
   2. Juxtaglomerular Feedback. Involves the Juxtaglomerular apparatus. Macula
       Densa cells which sense osmolarity and flow of urine in distal collecting duct.
       GFR is modulated depending on urine osmolarity and flow.
   3. Sympathetic Nervous system. More concerned with regulating blood volume and
       pressure. This is achived by changing GFR. Sympathetic nervous system
       through baroreceptor reflex tends to decrease GFR by causing vasocontriction of
       afferent and efferent arterioles
Tubular Reabsorption

   Organic nutrients such as glucose are completely reabsorbed into the peritubular
    capillaries and are not subject to homeostatic mechanisms that regulate their
    reabsorption rates.
   Although most of the water and electrolytes are reabsorbed they are regulated by
    neural and hormonal homeostatic mechanisms.
   Waste metabolites are only partially reabsorbed
   Tubular reabsorption occurs via two process‟.
    1. Diffusion:
    Substances (urea and lipid soluble compounds) in the proximal tubule move down
    their respective concentration gradients into the pertitubular capillary. The
    concentration gradients are established by the movement of water into the proximal
    tubule. The movement of fluid from the ISF into the pertibular capillaries occurs via
    Starling Forces.
    2. Mediated transport
    Substances moving from the tubular lumen to the peritubular capillaries against their
    electrochemical gradient move via transcellular epithelial transport.

    Transcellular Epithelial Transport

Transcellular epithelial transport involves the movement of molecules through two
membranes: The luminal membrane (lumen side) and the basolateral membrane (plasma
side). The characteristics of these two membranes are different in terms of their
complement of ion channels and transport proteins. The electrochemical gradients for the
molecules which are moved are also different with respect to the concentrations in the
lumen, epithelial cell and plasma side.
 The movement of Na+ ion from the lumen to the epithelial cell occurs via diffusion
    through a Na+ channel in the luminal membrane of the epithelial cell. The movement
    of Na+ out of the epithelial cell and into the ISF and hence the plasma occurs through
    the Na+ / K+ ATPase transporter (ie active transport of Na+) located in the basolateral
 The movement of glucose and amino acids against their concentration gradient from
    the lumen into the epithelial cell is coupled to the movement of Na+ ions down their
    concentration gradient. Movement of glucose and amino acids out of the epithelial
    cell, across the basolateral membrane and into the ISF and hence the plasma occurs
    via facilitated diffusion. Again, the movement of Na+ ions out of the cell across the
    basolateral membrane occurs via the Na+ / K+ ATPase transporter.
    As with any carrier mediated transport mechanisms there is a maximal rate at which a
    substance can be transported (Transport maximum, Tm). This is dependent on the
    concentration of the molecule and number of transport protein molecules available to
    transport it. People with diabetes mellitus have a high plasma glucose concentration
    and often exceed the Tm for glucose and have glucose appearing in their urine
 The net movement of water across the luminal and basolateral membranes and across
    the tight junctions between epithelial cells occurs via osmosis. However, it should be
    noted that osmosis is made possible by the active movement of electrolytes
    (particularly of Na+ ions) out of the epithelial cell across the basolateral membrane.
    This is called the „solvent drag‟ phenomena and is the basis for the Golden Rule
    “Water follows Sodium”

Tubular Secretion

   Tubular secretion like tubular reabsorption occurs via diffusion and mediated
    diffusion (transcellular epithelial transport).
   Ions such as H+, K+ organic anions and drugs are actively secreted.
   The epithelial cells also metabolise a variety of compounds and secrete them into the
    tubular lumen (eg. ammonium ion)
   The number of transport proteins in the luminal or basolateral membranes for tubular
    reabsorption or secretion is regulated by neural and hormonal factors. This provides a
    means by which the tubular reabsorption and secretion of a molecule is controlled.

Sodium and Water Reabsorption

  Normally, Na+ and water losses are exactly equal to sodium and water gains. This
   matching of inputs with outputs is achieved through the regulation of urinary loss.
 Na+ and water are reabsorbed via two process‟:
1. Na+ reabsorption is an active process in all tubules except in the descending limb of
   the Loop of Henle. The mechanism by which Na+ diffuses across the luminal
   membrane of the epithelial cell differs along the tubule. In some areas Na+ diffuses
   through Na+ channels, Na+ / glucose co-transporter, or Na+ / H+ counter transporter.
   The mechanism by which Na+ is moved out of the epithelial cell across the
   basolateral membrane is always via the Na+ / K+ ATPase.

2. Water reabsorption is always via diffusion but is dependent on Na+ reabsorption. The
   net movement of water across the luminal and basolateral membranes (through
   aquaporins) and across the tight junctions between epithelial cells occurs via osmosis.
   However, it should be noted that osmosis is made possible by the active movement of
   Na+ out of the epithelial cell across the basolateral membrane. The electrochemical
   gradient created by the movement of Na+ establishes a gradient by which osmosis can
   occur. The water permeability of the proximal tubule is the highest as a consequence
   most of the Na+ is reabsorbed here.

   The water permeability of the cortical and medullary collecting ducts is controlled by
    antidiuretic hormone (ADH) also known as vassopressin.
   ADH stimulates the insertion of an aquaporin into the luminal membrane of epithelial
    cells lining the cortical and medullary collecting ducts and enhances water
   Deficiencies in ADH lead to a water diuresis and is the underlying cause of diabetes
The Counter Current Multiplier

   The kidneys can produce urine with an osmolarity of up to 1400mOsm/litre. This is
    five times the osmolarity of plasma.
   This concentrated urine is achieved through the interaction of the counter current
    multiplier system (Loop of Henle), the action of ADH on medullary and cortical
    collecting ducts and the unique anatomy of the blood vessels within the medulla (vasa
   Fluid entering the Loop of Henle from the proximal tubule is isoosmotic with the
   The descending Loop of Henle is permeable to water. The ascending Loop is
    impermeable to water while it pumps out Na and Cl ions.
   The whole point is to create an osmolarity gradient in the ISF down through medulla
    region of the kidney. As a consequence of this osmotic gradient, water can move out
    into the ISF (if ADH is present) and be reabsorbed. This creates hyperosmotic urine.
   If ADH is not present all the water stays in the collecting ducts and is lost in the
    urine. This urine is hypoosmotic.
   The vasa recta (blood vessels within the medulla) runs in parallel to the Loop of
    Henle and ensures that the osmotic gradient in the medullary ISF is maintained.

Renal Sodium Regulation

   The regulation of total body Na+ is achieved through the baroreceptors and
    As Na+ is the major electrolyte in plasma, any change in Na+ ion concentration will
    affect plasma volume and hence blood pressure. Low Na+ concentration will
    ultimately lead to low blood pressure. Low blood pressure activates the baroreceptor
    reflex. An increase in the activity of sympathetic nerves causes a constriction of the
    renal arterioles that lowers GFR and increases Na+ reabsorption.
   The renin-angiotensin system acts to stimulate the secretion of aldosterone from the
    adrenal cortex. Aldosterone increases the reabsorption of Na+ ions by the collecting
    ducts by promoting the expression and synthesis of the transport proteins involved in
    moving Na+ ions. That is, aldosterone promotes the expression and synthesis of Na+
    channels and the Na+ / K+ ATPase on the luminal and basolateral membranes

   Stimulation of the renal sympathetic nerves (as a result of the initiation of the
    baroreceptor reflex) stimulate the juxtaglomerular cells to release renin.
   The juxtaglomerular cells are sensitive to pressure and constitute intrarenal
    baroreceptors. A reduction in renal blood pressure (as a result of low Na+) stimulates
    the juxtaglomerular cells to release renin
Renal Water Regulation

   ADH is the major hormone controlling water reabsorption.
    NOTE: The baroreceptor reflexes and renin-angiotensin system will also regulate
    water reabsorption as a the movements of water are associated with Na+
   ADH release from the posterior pituitary is stimulated by osmoreceptors located in
    the hypothalamus. An increase in total body water leads to a reduction in body fluid
    osmolarity. This causes a decreased firing of the hypothalamic osmoreceptors and a
    decreased release of ADH from the posterior pituitary.

Hydrogen Ion Regulation / Acid Base

   Enzyme mediated reactions are highly sensitive to changes in pH. As a consequence
    the concentration of H+ ions is closely regulated.
   H+ ions are continually added to the plasma. These sources include:
    1. Carbonic acid formation
    2. Acids produced from the metabolism of proteins and other organic molecules
    3. Loss of bicarbonate ions (HCO3-) from GI tract and urine (the loss of one
        bicarbonate ion is effectively equal to the gain of one H+ ion)
   H+ ions are continually lost from the plasma. These sources include:
    1. Utilisation of H+ ions in metabolism if organic anions
    2. Loss of H+ from vomiting and urine
    3. Hyperventilation
   Large changes in the plasma pH are prevented by buffer systems. A buffer system is
    composed of two compounds that minimize pH when an acid or base is added or
    removed from the plasma..
   There are four buffer systems in the body:
    1. The carbonic acid/bicarbonate system
    2. The protein buffer system
    3. The hemoglobin buffer system
    4. The phosphate buffer system
   The regulation of plasma pH by the kidneys is achieved through the interaction of
    tubular secretion of H+ ions and ISF secretion of bicarbonate ions.

   If there are excess H+ ions in the lumen after all of the bicarbonate ions have been
    used a non bicarbonate (phosphate buffer system) buffer combines with the H+ ions.
   When non bicarbonate buffer combines with secreted H+ ions in the lumen a net gain
    of bicarbonate ions results.
   Bicarbonate ions are also produced by tubular epithelial cells from glutamine.
    Glutamine is absorbed from the glomerular filtrate in the tubular lumen or from the
    ISF and is converted to ammonium ions and bicarbonate ions. The ammonium ions
    are secreted across the luminal membrane and into the lumen via Na+ / ammonium
    counter transport and the bicarbonate ions diffuse across the basolateral membrane
    and into the ISF through a transport protein.
   The renal responses to metabolic / respiratory alkalosis / acidosis will involve
    changes in the rates of the above mechanisms to compensate for an increase /
    decrease in blood pH.

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