I’m Still Not Feeling Well (PBL 2)
PBL Learning Objectives
Describe the anatomical and physiological determinants of glomerular filtration rate and
renal blood flow
Glomerular filtration rate (GFR) and renal blood flow (RBF) are intimately related.
Anatomical Determinants of Renal Blood Flow
Blood Supply
Each kidney receives about 10% of the total blood volume per minute (receive 1200 mL/min) via the large
renal arteries, which are lateral branches of the abdominal aorta, just inferior to the origin of the superior
mesenteric artery (L1-L2). The right renal artery is longer and passes posterior to the IVC. The renal artery
divides into five separate segmental arteries, which then move into the different segments of the kidneys
and do not anastomose with each other. This results in distinct vascular segmentation of the kidney, with
each being surgically resectable. Several renal veins drain each kidney and unite in a variable fashion to
form the right and left renal veins, which lie anterior to the right and left renal arteries. To note:
 Efferent arterioles arising from cortical nephrons divide into two peritubular capillaries that surround
the proximal (PCT) and distal convoluted tubules (DCT), forming a rich meshwork of microvessels
(which function to remove water and solutes from renal tubule). This drains into the interlobular veins.
 Efferent arterioles arising from juxtamedullary nephrons (nephrons closest to medulla) give rise to
vasa recta, which descends with the loop of Henle into the renal medulla and return to area of
glomerulus before draining into interlobular or arcuate veins
- Each vasa recta carrier blood at a very slow rate, which is crucial in countercurrent exchange that
prevents the washout of concentration gradients established in the urine. Gradient maintenance is
important in the kidney’s ability to concentrate urine.
- On the descending part of vasa recta, NaCl and urea are reabsorbed into the blood and water is
secreted. On the ascending portion of vasa recta, NaCl and urea are secreted into the interstitium
and water is reabsorbed
The Renal Corpuscle and the Glomerulus
The nephron is the basic unit of kidney structure and function, each containing a:
1. Renal corpuscle, which filters fluid from the blood. The renal corpuscle consists of a compact tuft of
interconnected capillary loops, the glomerulus, surrounded by a hollow capsule (Bowman’s Capsule).
2. A long, renal tube that converts filtered fluid into urine
The glomerulus is an anastomosing network of capillaries composed of fenestrated endothelial cells. The
capillaries have a high hydrostatic pressure (~60 mmHg) that causes rapid fluid filtration.
The renal corpuscle has a urinary pole (proximal tube attaches to the glomerulus) and a vascular pole
(arterioles attach and macula densa is located).
 The urinary pole is where there is an abrupt change (but continuous) from flat epithelial cells of
Bowman’s capsule to cuboidal epithelial cells of PCT.
 The vascular pole is where the glomerulus is connected to afferent and efferent arterioles. Afferent
arterioles are larger than efferent to help maintain filtration pressure within glomerulus. Arterioles are
associated with juxtaglomerular, which is composed of:
- Macula Densa consists of closely spaced epithelial cells of the distal tubule. These cells sense
sodium concentration in the tubular lumen.
- Juxtaglomerular Cells are modified smooth muscle cells found mainly in the afferent arteriole,
which sense pressure changes in the arterioles and secrete renin.
- Lacis Cells (Mesangial Cells) which have an uncertain role but may produce erythropoietin.
The Glomerular Filtration Barrier
The filtration barrier in the renal corpuscle, through which all filtered substances must pass has:
1. The endothelial cells of the capillaries are perforated by many large fenestrae. Although these
fenestrations are fairly large, the endothelial cells are well endowed with fixed negative charges that
hinder the passage of plasma proteins.
2. The basement membrane/basal lamina, which is consists of a meshwork of collagen and
proteoglycans fibrillae that have large spaces through which large amounts of water and small solutes
can filter. This basement membrane effectively prevents the filtration of plasma proteins due to the
strong negative electrical charges associated with proteoglycans.
3. The podocytes (epithelial cells) that rest of the basement membrane and face Bowman’s space. They
are attached to the basement membrane via foot processes, which have filtration slits (25-60 nm
diameter) present between them.
4. This final layer is not continuous, but sends long secondary members that encircle the outer surface of
the capillaries. The secondary members are separated by gaps called slit pores through which the
glomerular filtrate moves. These epithelial cells, which also have negative charges, provide additional
restriction to the filtration of plasma proteins
Physiological Determinants of GFR- Glomerular Filtration and GFR
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The glomerular filtration process results in the formation of an ultrafiltrate of plasma
A key function of the glomerulus is to act as a filtration barrier that permits the passage of water and
other solutes and restricts the movement of certain molecules. Selectivity of filtration is dependent on
molecule size, as well as charge
Glomerular filtration rate (GFR) describes the flow rate of filtered fluid through the kidney. It is equal
to the sum of all the filtration rates of all the functioning nephrons, and as such, is an index of kidney
function
In normal adults, the GFR averages 90-140 mL/min for males, and 80-125 mL/min for females. Thus,
approximately 180L/day of plasma is filtered at the glomerulus. The GFR is determined by:
- The balance of hydrostatic and colloid osmotic forces acting across the capillary (net filtration
pressure)
- The glomerular capillary coefficient (KP), which is the product of the permeability and filtering
surface area of the capillaries. The normal KP is about 12.5 mL/min/mmHg of filtration pressure.
GFR= KP x Net Filtration Pressure
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Ultrafiltration occurs because Starling forces (i.e. hydrostatic and oncotic pressures) drive fluid from
the lumen of the glomerular capillaries, across the filtration barrier, and into Bowman’s space:
- Hydrostatic pressure inside the glomerular capillaries, which promotes filtration of fluid into
Bowman’s space
- Hydrostatic pressure in Bowman’s capsule outside the capillaries, which opposes filtration
- Colloid osmotic pressure of the glomerular capillary plasma proteins, which opposes filtration
- Colloid osmotic pressure of the proteins in Bowman’s capsule The glomerular ultrafiltrate is
essentially protein free and the oncotic pressure in Bowman’s space is essentially zero
In this way, the GFR can be altered by changing KP or any of the Starling forces
 Increased KP raises GFR and vice versa- Some diseases lower KP by reducing the number of functional
glomerular capillaries, lowering the surface area for filtration
 Increasing Bowman’s Capsule Hydrostatic Pressure Decreases GFR and vice versa- In certain
pathological states associated with obstruction of the urinary tract, Bowman’s capsule pressure can
increase markedly
 Increasing glomerular capillary colloid oncotic pressure, decreases GFR- Increasing arterial plasma
colloid oncotic pressure or increasing the filtration fraction (fraction of plasma filtered by glomerular
capillaries) raises the glomerular colloid osmotic pressure  decreasing GFR, as there is an increased
tendency to keep fluid in the capillaries
 Increased glomerular capillary hydrostatic pressure increases GFR- Changes in glomerular hydrostatic
pressure serve as the primary means for physiologic regulation of GFR.
- The GFR is governed by three interplaying factors in regards to the afferent and efferent arterioles
of the nephron.
- The aortic pressure perfusing the kidney (kidney perfusion)- Increased arterial pressure tends to
raise glomerular hydrostatic pressure, and therefore, increase GFR. However this effect is buffered
by autoregulatory mechanisms that maintain a relatively constant glomerular pressure as blood
pressure fluctuates.
- Increased resistance of afferent arterioles reduced glomerular hydrostatic pressure and decreases
GFR, as it determines the degree of renal arterial pressure transmitted to the glomerulus.
- Constriction of the efferent arterioles increases the resistance to outflow from the glomerular
capillaries. This raises the glomerular hydrostatic pressure, but also reduces renal blood flow,
causing the filtration fraction and glomerular colloid osmotic pressure increase as efferent
arteriolar resistance. Thus, efferent arteriolar constriction has a biphasic effect on GFR. At
moderate levels of constriction, there is a slight increase in GFR, but with severe constriction, there
is a decrease in GFR
- A fall in resistance to outflow from effect glomerular capillaries decreases the glomerular capillary
hydrostatic pressure, and thus decreases GFR
Renal Blood Flow and Oxygen Consumption
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The kidneys normally consume oxygen at twice the rate of the brain but have almost seven times the
blood flow of the brain. Thus, the oxygen delivered to the kidneys far exceeds their metabolic needs,
and the arterial-venous extraction of oxygen is relatively low compared with that of most other tissues.
A large fraction of the oxygen consumed by the kidneys is related to the high rate of active sodium
reabsorption by the renal tubules – i.e. if renal blood flow and GFR are reduced and less sodium is
filtered, less sodium is reabsorbed and less oxygen is consumed
The outer part of the kidney, the renal cortex, receives most of the kidney’s blood flow (98-99%)
Flow to the renal medulla is supplied by a specialized portion of the peritubular capillary system called
the vasa recta
Determinants of Renal Blood Flow
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Renal blood flow is determined by the pressure gradient across the renal vasculature:
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Renal artery pressure is about equal to systemic arterial pressure, and renal vein pressure averages
about 3 to 4 mm Hg under most conditions
Most of the renal vascular resistance resides in three major segments: interlobular arteries, afferent
arterioles, and efferent arterioles. Resistance of these vessels is controlled by the sympathetic
nervous system, various hormones, and local internal renal control mechanisms. An increase in the
resistance of any of the vascular segments of the kidneys tends to reduce the renal blood flow,
whereas a decrease in vascular resistance increases renal blood flow if renal artery and renal vein
pressures remain constant..
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Autoregulation of Renal Blood Flow and GFR
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Feedback mechanisms intrinsic to the kidneys normally keep the renal blood flow and GFR relatively
constant, despite marked changes in arterial blood pressure (autoregulation)
Autoregulatory mechanisms aim to preserve changes in arterial blood pressure, which are the
essential driving forces for glomerular filtration
This ensures precise control of renal excretion of water and solutes
Two mechanisms are responsible for autoregulation of RBF and GFR: one mechanism that responds to
changes in arterial pressure (myogenic mechanism), and another that responds to changes in the NaCl
concentration of tubular fluid (tubuloglomerular feedback)
The Role of the Tubuloglomerular Feedback in Autoregulation of GFR
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To perform the function of autoregulation, the
kidneys have a feedback mechanism that links
changes in sodium chloride concentration at the
macula densa with the control of renal arteriolar
resistance
This feedback helps ensure a relatively constant
delivery of sodium chloride to the distal tubule
and helps prevent spurious fluctuations in renal
excretion that would otherwise occur
The tubuloglomerular feedback mechanism has
two components that act together to control
GFR:
- An afferent arteriolar feedback mechanism
- An efferent arteriolar feedback mechanism
These feedback mechanisms depend on special
anatomical arrangements of the juxtaglomerular
complex, which consists of macula densa cells in
the initial portion of the distal tubule and
juxtaglomerular cells in the walls of the afferent
and efferent arterioles
The macula densa cells sense changes in volume delivery to the distal tubule by way of signals that are
not completely understood. Studies suggest that decreased GFR slows the flow rate in the loop of
Henle, 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
This decrease in sodium chloride concentration initiates a signal from the macula densa that has two
effects:
- It decreases resistance to blood flow in the afferent arterioles, which raises glomerular hydrostatic
pressure and helps return GFR toward normal
- It increases renin release from the juxtaglomerular cells of the afferent and efferent arterioles.
Renin released from these cells increases the formation of angiotensin I, which is converted to
angiotensin II. Finally, the angiotensin II constricts the efferent arterioles, thereby increasing
glomerular hydrostatic pressure and returning GFR toward normal
Myogenic Autoregulation of Renal Blood Blow and GFR
 Another mechanism that contributes to the maintenance of a relatively constant renal blood flow and
GFR is the ability of individual blood vessels to resist stretching during increased arterial pressure, a
phenomenon referred to as the myogenic mechanism.
 Individual blood vessels (especially small arterioles) throughout the body respond to increased wall
tension or wall stretch by contraction of the vascular smooth muscle
 Stretch of the vascular wall allows increased movement of calcium ions from the extracellular fluid into
the cells, causing them to contract
 This contraction prevents over distension of the vessel and at the same time, by raising vascular
resistance, helps prevent excessive increases in renal blood flow and GFR when arterial pressure
increases.
Sympathetic Nervous System Activation Decreases GFR
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Essentially all the blood vessels of the kidneys, including the afferent and the efferent arterioles, are
richly innervated by sympathetic nerve fibres
Strong activation of the renal sympathetic nerves can constrict the renal arterioles and decrease
renal blood flow and GFR
Moderate or mild sympathetic stimulation has little influence on renal blood flow and GFR i.e. reflex
activation of the SNS resulting from moderate decreases in pressure at the carotid sinus baroreceptors
has little influence on renal blood flow or GFR.
The renal sympathetic nerves seem to be most important in reducing GFR during severe, acute
disturbances lasting for a few minutes to a few hours, such as those elicited by the defence reaction,
brain ischemia, or severe hemorrhage
In the healthy resting person, sympathetic tone appears to have little influence on renal blood flow.
Angiotensin II Constricts Efferent Arterioles
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Angiotensin II is produced systemically and within the kidney
It constricts the afferent and (mainly) efferent arterioles and decreases RBF and GFR
Angiotensin-converting enzyme (ACE) degrades and thereby inactivates bradykinin and converts
angiotensin I, an inactive hormone, to angiotensin II. Thus, ACE increases angiotensin II levels and
decreases bradykinin levels
Drugs called ACE inhibitors, which reduce systemic blood pressure in patients with hypertension,
reduce angiotensin II levels and elevate bradykinin levels. These effects lower systemic vascular
resistance, reduce blood pressure, and decrease renal vascular resistance. ACE inhibitors therefore
increase RBF and GFR
Fall in renal perfusion pressure
Activation of renin-angiotensin system
AT2 preferentially locally increases resistance at efferent arteriole = vasoconstriction
Preservation of GFR in hypotension
Neurohumoral Influences
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Sympathetic stimulation can also cause vasoconstriction due to stimulation of alpha-1-adrenergic
receptors by noradrenaline. Reduced renal perfusion pressure in patients is most often due to
depletion of effective circulating volume (e.g. hypovolemia or dehydration), causes systemic
hypoperfusion, which leads to increased release of vasoconstrictors AT2 and Noradrenaline. As
mentioned, AT2 increases efferent arteriole resistance; whereas noradrenalin increases tone in both
arterioles. The net effect is renal vasoconstriction in order to shunt blood to the critical coronary and
cerebral circulations whilst maintaining GFR (sympathetic response).
Hormone
Mechanism
Final Effect
Noradrenaline
Angiotensin II
Endothelin
Prostaglandins
(E and I)
Nitric Oxide
Bradykinin
Atrial Natriuretic
Peptide
Glucocorticoids
Dopamine
Histamine
Vasoconstriction of afferent and efferent arterioles
In low concentrations, constricts efferent arteriole, in high
concentrations constricts both
Secreted by endothelial cells of renal vessels causing
vasoconstriction of afferent and efferent arterioles. It
contributes to haemostasis when a blood vessel is
severed, when the endothelium is damaged.
Produced locally in kidneys during conditions such as
haemmorrhage. They inhibit vasoconstrictive role of
sympathetic stimulation and angiotensin II
RBF/GFR
 RBF/GFR
Vasodilates afferent and efferent arterioles
Stimulates release of prostaglandins and NO
As heart is stretched due to increased cardiac load, atrial
cells secrete ANP which dilates afferent and efferent
arterioles
 RBF/GFR
 RBF/GFR
 RBF/GFR
Produced by proximal tubule and increases RBF and
inhibits rennin secretion
Decreases resistance of afferent and efferent arterioles
 RBF/GFR
 RBF/GFR
 RBF/GFR
 RBF/GFR
 RBF/GFR
Describe the function of the renal tubules, i.e. Reabsorption, secretion and urine
concentration
Overview
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Out of the 180 L of glomerular filtrate former per day, about 1.5 L (<1%) is excreted as urine.
Selective reabsorption and absorption of solutes and water along the renal tubule facilitate this low
urine output.
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The tubules precisely control volume, osmolality, composition and pH of intracellular and
extracellular fluid compartments.
Transport mechanisms across cell membrane:
- Passive Transport
 Simple Diffusion along electrochemical gradients (both in charge and concentration) and
can follow either a transcellular or intercellular route
 Facilitated diffusion, where the movement of one solute along an electrochemical gradient
facilitates the movement of another against its electrochemical gradient.
- Active Transport
 This involves movement of an ion against electrochemical gradient, which requires energy
expenditure.
The two central functions of renal tubules are:
- Tubular reabsorption- active transport of solutes e.g. glucose, amino acids, electrolytes and
vitamins from glomerular filtrate, through the tubular lumen and into peritubular capillaries
- Tubular Secretion- transport of solutes from peritubular capillaries into tubular lumen
Proximal Tubular Transport
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This region of the nephron has a high energy consumption and:
1) Is the “workhorse” of sodium and water reabsorption (65-75% of the filtered load)
2) Reabsorbs almost all filtered glucose, phosphate, amino acids and other organic solutes by linking
their transport to glucose
PCT cells are characterised by brush borders on their luminal surfaces, composed of thousands of villi
which increase the absorptive surface area significantly. Absorbed substances are transferred to the
peritubular capillaries from the basolateral membrane of the cell.
Sodium Ion Reabsorption- This is done through a combination of active and passive transport, though
mainly active via a basolateral Na+-K+-ATPase pump, which sets up an electrochemical gradient for
passive solute diffusion, osmosis and secondary active transport (cotransport) with Na +. It pumps 3Na+
out of cell and 2 K+ into cell The combination of low [Na+] and cell-interior negative potential results in
favorable electrochemical gradient for sodium entry into the cell across the apical membrane
- In the early PCT, Na+, glucose and other organic solutes, enter the cell with Na + and leave the cell
across the basolateral membrane by passive transport mechanism. Na + is reabsorbed by
cotransport with H+ or organic solutes (glucose, amino acids, phosphate and lactate).
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In the late PCT, Na+ is absorbed via chloride-driven sodium transport mechanism across both
transcellular and paracellular pathways. In the paracellular pathway, the high concentration of Cl- in
the late PCT creates a concentration gradient that facilitates diffusion of Cl - with Na+ through the
PCT cell. In the transcellular pathway, Na+ reabsorption occurs via parallel operation of Na +H+ and
one or more Cl- anion (formate) antiporters.
 The transporter results in secretion of H+ ion into the tubular lumen in exchange for a Na+.
Much of the secreted H+ then combines with bicarbonate, leading to the reabsorption of
90% of filtered bicarbonate
Osmotic water transport occurs due to the high permeability of apical and basolateral membranes to
water due to presence of aquaporins (transmembrane water channels). The removal of solutes from
the lumen initially lowers tubular fluid osmolality, thereby creating an osmotic gradient, which
promotes an equivalent degree of water reabsorption. Water reabsorption also occurs between the
cells across leaky tight junctions on the proximal tubule. The sodium concentration and osmolality of
the fluid leaving the proximal tubule is the same as that of plasma
Disorders in proximal tubule transport are quite rare, and are associated with:
- Glycosuria
- Amino aciduria
- Type 2 “proximal” renal tubular acidosis (impaired acid excretion)
Loop of Henle
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This region of the nephron reabsorbs approximately 20-25% of the filtered Na+ (and thus Cl-) and is
relatively impermeable to water movement (lacking aquaporins). As a result, solutes are reabsorbed
in greater quantity than water, diluting the tubular fluid and increasing the solute concentration of
the medulla, contributing to the concentrating function of the collecting duct.
Thin Descending Limb- Water absorption occurs passively (due to hypertonic interstitial fluid)
exclusively in this part of the Loop of Henle. This is accompanied by diffusion of Na + ions from
interstitial fluid into tubular lumen.
Thin Ascending Limb – Limited passive reabsorption of Na + and Cl-.
Thick Ascending Limb – impermeable to H2O but reabsorbs 20-25% of filtered Na +, Cl- and other
cations.
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Na+, K+, 2Cl- cotransporter mediated active transport of sodium.
Site of action of Loop Diuretics (e.g. furosemide) which inhibit the Na+, K+, 2Cl- cotransporter
Paracellular passive reabsorption of Na+, K+, Ca2+ and Mg2+ between cells across tight junction
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Chloride exits the cell through a basolateral channel
Distal Tubule
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Distal tubule reabsorbs 5-8% of filtered sodium chloride and is relatively impermeable to water,
leading to a fall in [Cl-]. This limits sodium chloride reabsorption in the Loop of Henle and distal tube.
- Activity of Na-K-2Cl and Na-Cal cotransporters is primarily determined by luminal chloride
concentration. Thus, a reduction in chloride concentration will reduce rate of sodium chloride entry
into the cell. This is because the binding of chloride to this transporter induces a conformational
change that is required for solute movement into the cell
- Sodium chloride concentration in the peritubular interstitium is similar to plasma. Hence, falling
concentration within the lumen creates a favourable concentration for backflux of sodium and
chloride into lumen across tight junctions. Reabsorption ceases when the rate of sodium entry into
the cell equals the rate of backflux
The major site of urine dilution is the cortical diluting segment, where solutes are absorbed more than
water.
The electrochemical gradient is driven by the Na+-K+ ATPase, with a luminal Na+-Cl- cotransporter.
Thiazide diuretics block the Na+-Cl- cotransporter, which may lead to excessive dilution of body fluids
Calcium Transport- Distal tubules has major sites at which urinary calcium excretion is actively
regulated under the influence of parathyroid hormone and vitamin D
Collecting Duct
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There are two distinct cell types:
- Principal
- Intercalated (type A and type B)
This region of the nephron is responsible for concentrating the urine (i.e. water reabsorption), as well
as acid and potassium excretion.
Vasopressin stimulates the insertion of water channels (aquaporin’s) into the luminal and basal
membranes, and hence water is absorbed across the epithelium layer.
Principal Cells- In the cortical collecting tubule and the cells in the inner medullar collecting duct play an
important role in sodium and water reabsorption and potassium secretion
Solute Transport in the Principal Cell
 The electrochemical gradient is driven by the Na+-K+ ATPase pump, where the principal cell has an
overall negative charge, excess potassium and relative deficiency of sodium.
 Sodium is absorbed into the cell via a luminal transporter, hence transferring the negative charge to
the lumen. Potassium then leaves via the apical and luminal channels (luminal excretion is favoured by
the negative charge).
 Expression of both channels is under the control of aldosterone, a hormone which increases DNA
transcription and also ANP, which decreases Na+ reabsorption by reducing the number of open Na+
channels.
Intercalated cells- In the cortex and the cells in the outer medulla are primarily involved in the regulation
of acid-base balance
Transport in the Type A Intercalated Cell
 These cells are used to excrete H+ ions into the urine via:
- Active H+ pump
- K+-H+ exchanger (plays only a minor role)
 On the basolateral membrane, the Cl--HCO3- exchanger is used to reabsorb bicarbonate back into the
bloodstream. The net effect is excretion of H+ ions, thereby acidifying the urine.
Transport in the Type B Intercalated Cell
This is simply the “mirror image” of the type A intercalated cell. These cells are used to excrete
bicarbonate and reabsorb hydrogen, with the net effect being reabsorption of H + ions from the urine.
Describe the renal actions and regulation of the renin-angiotensin system, prostaglandins
and atrial natriuretic peptide
Overview
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The renin-angiotensin-aldosterone axis promotes Na+ retention through the actions of both
angiotensin II and aldosterone. It plays an important role in regulating blood volume and systemic
vascular resistance, which together influence cardiac output and arterial pressure
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It is regulated by the mechanisms that stimulate renin release
Angiotensinogen, and Angiotensin I and II
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Angiotensinogen is synthesised by the liver and released into the systemic circulation. The liver
contains only small stores of Angiotensinogen
Another protein, renin, is produced and stored in distinctive granules by the granular cells of the
juxtaglomerular apparatus. Decreases in effective circulating volume stimulate these cells to release
renin. This protease cleaves Angiotensinogen, thereby releasing angiotensin I (ANG I)
Angiotensin-converting enzyme (ACE) rapidly removes two C-terminal amino acids from the
physiologically inactive ANG I to form ANG II. ACE is present on the luminal surface of vascular
endothelium throughout the body, and is abundantly present in endothelium-rich lungs. ACE in the
kidney. particularly in the endothelial cells of the afferent and efferent arterioles, can produce enough
ANG II to exert local vascular effects
Thus, the kidney receives ANG II from two sources:
- Systemic ANG II comes from the general circulation and originates largely from the pulmonary
region
- Local ANG II forms from the renal conversion of systemic ANG II
Renin Release
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The principal factor controlling plasma ANG II levels is renin release from JGA granular cells
A decrease in effective circulating volume manifests itself to the JGA, and thus stimulates renin release
in three ways:
Decreased systemic blood pressure:
- A low effective circulating volume, sensed by baroreceptors located in the central arterial
circulation, signals medullary control centres to increase sympathetic outflow to the JGA, thus
increasing renin release
- Renal denervation or β-adrenergic blocking drugs (e.g. propanolol) inhibit renin release
Decreased NaCl concentration at macula densa (NaCl sensor):
- Independent of renal nerve activity or renal perfusion pressure, decreased effective circulating
volume decreases GFR and thus reduces luminal [NaCl] at the macula densa, thereby increasing renin
release
Decreased renal perfusion pressure (renal baroreceptor):
- Stretch receptors in the granular cells of the afferent arterioles sense the decreased distension
associated with low effective circulating volume
- This decreased stretch lowers [Ca2+]I, thereby increasing renin release and initiating a cascade that
tends to increase blood pressure
- Conversely, increased distension (higher extracellular volume) inhibits renin release
Some additional factors also modulate renin release:
- Prostaglandins E2 and I2 and endothelin all activate renin release
- Agents that blunt renin release ANG II (which represents a short feedback loop), AVP, thromboxane
A2, high plasma levels of K+ and NO
Actions of Angiotensin II
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Stimulation of Aldosterone release from glomerulosa cells in the adrenal cortex:
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Aldosterone tends to promote Na+ and water retention and lowers plasma K+ concentration. It
acts on the principal cells in the distal tubule and the collecting duct, up-regulating and activating
the basolateral Na+-K+ pumps, hence increasing Na+ reabsorption (and water) into the blood and
secreting K+ into the urine.
- In animal models, unopposed aldosterone infusion causes increased glomerulosclerosis and severe
proteinuria through a non-epithelial profibrotic effect on the kidney. The aldosterone component
of RAAS can be targeted with mineralocorticoid receptor blockers, offering benefits additive to the
therapy of ACE inhibitors.
Vasoconstriction of renal and other systemic vessels:
- ANG II increases Na+ reabsorption by altering renal haemodynamics, probably in two ways
- First, at high concentrations, ANG II constricts the efferent more than the afferent arterioles, thus
increasing filtration fraction and reducing the hydrostatic pressure in the downstream peritubular
capillaries. The increased filtration fraction also increases the protein concentration in
downstream blood and hence raises the colloid osmotic pressure of the peritubular capillaries. This
favours the uptake of reabsorbate from the peritubular interstitium into peritubular capillaries, and
hence enhance the reabsorption of Na+ and fluid by the proximal tubule
- Second, ANG II decreases medullary blood flow through vasa recta. This decreases medullary
washout of NaCl and urea, a process that raises [urea] in the medullary interstitium and enhances
Na+ reabsorption along the thin ascending limb of Henle’s loop
 ANG II works by binding to AT1 receptors at the apical and basolateral membranes of
proximal tubule cells, and stimulating apical NHE3s
 ANG II also stimulates Na-H exchange in the thick ascending limb (TAL) and stimulates apical
Na+ channels in the initial collecting tubule
 These effects promote sodium reabsorption
Enhanced tubuloglomerular feedback:
- ANG II raises the sensitivity and lowers the set point of the tubuloglomerular feedback mechanism,
so that an increase in Na + and fluid delivery to the macula densa elicits a much more pronounced
fall in the GFR
Enhanced Na-H exchange:
- ANG II promotes Na+ reabsorption in the proximal tubule, thick ascending limb (TAL), and initial
collecting tubule
Renal hypertrophy:
- ANG II induces hypertrophy of renal tubule cells
Stimulated thirst and AVP (ADH/vasopressin) release:
- ANG II acts on the hypothalamus, where it increases the sensation of thirst and stimulates
secretion of ADH from the posterior pituitary, both of which increase total body free water
- This ANG II effect represents an intersection between the systems for regulating effective
circulating volume and osmolality
 ADH acts by binding to a V2 receptor at the basolateral membrane of target cells, which
increases cAMP
 In the TAL, ADH stimulates the apical NKCC2 and K + channels
 In principal cells, ADH stimulates Na+ transport by increasing the number of open Na+
channels in the apical membrane
ACE Inhibitors


These drugs are used to control hypertension by decreasing the overall levels of angiotensin II. It has
several tissue and renal effects:
- Reverse hypertrophy and vascular remodelling in hypertensive disease
- Reverse rarefaction in vascular disease
- Decrease protein excretion in many renal diseases
- Decrease the production of aldosterone (acutely)
- Limit aldosterone’s capacity for potassium excretion (in exchange for sodium in the distal tubule)
The drug almost invariably decreases renal plasma flow and the GFR.
Angiotensin Receptor Antagonists
These drugs decrease the tissue efficacy of angiotensin II. The overall effects include:
 Decrease cardiac remodelling
 Decrease GFR
 Decrease renal protein excretion
In general, drugs that act upon the renin-angiotensin-aldosterone system have a beneficial effect on
blood pressure, providing a 5-10 mmHg further reduction, whilst also reducing proteinuria by 30-55%.
However, there is a 0-10% risk of severe hyperkalaemia.
Atrial Natriuretic Peptide (ANP)



Of the main methods that correct a low circulating volume, ANP is the only one that does so by
decreasing its activity. It is as an important counter-regulatory system
As its name implies, ANP promotes natriuresis (i.e. Na+ excretion)
Atrial myocytes synthesise and store ANP and release ANP in response to stretch (a low-pressure
volume sensor). Thus, reduced circulating volume inhibits ANP release and reduces Na + excretion





ANP has many synergistic effects on renal haemodynamics and on transport by renal tubules that
promote renal Na+ and water excretion
Although ANP directly inhibits Na+ transport in the inner medullary collecting duct, its major actions are
haemodynamic- increased GFR, increased cortical and medullary blood flow, and decreased release
of renin and AVP. Increased flow to medullary interstitium decreases osmolality and ultimately reduces
passive Na+ reabsorption in the thin ascending limb
Thus, a decrease in effective circulating volume leads to a fall in ANP release and a net decrease in Na +
and water excretion
ANP binds to ANP-A-receptors on collecting duct cells and acts via cGMP to inactivate apical sodium
channels, so reducing sodium reabsorption
It also inhibits aldosterone release and renin production and increases GFR by dilating afferent
arterioles
Prostaglandins



Both COX-1 and COX-2 are present in the kidney in constitutive and inducible forms
The prostaglandins that are most important in the kidney are PGE2 and PGI2
- PGE2 decreases sodium reabsorption at the thick ascending limb of the loop of Henle
- PGI2 prostacyclin stimulates renin release, which in turns increases aldosterone. Prostacyclin is
also a strong vasodilator that maintains glomerular filtration rate (GFR) and renal blood flow in
patients with decreased actual or effective circulating volume, however the vasodilatory role of
PGI2 is not operative and has little importance in renal haemodynamics.
As a result of inhibiting PGE2, one may experience:
- Sodium retention, manifested as weight gain
- Peripheral oedema



- Congestive heart failure (rarely)
- Blood pressure may also increase because of sodium retention
This occurs most often in patients with hypertension who are being treated with antihypertensive
medications.
In addition, inhibition of PGI2 can cause hyperkalaemia or, in patients at risk for adverse renal effects,
acute renal failure
NSAIDs can be grouped into four categories:
1. Selective COX-1 inhibitors, such as aspirin
2. Non-selective COX inhibitors
3. Relatively selective COX-2 inhibitors
4. Highly selective COX-2 inhibitors
Describe the role of the kidney in acid-base and potassium balance, and the consequences
of hyperkalaemia
Acid-Base Balance
If pH deviates too far from the normal range, cells become poisoned by their own toxic waste and die.
Imbalanced pH interrupts all cellular activities and functions and can lead to the progression of most
degenerative diseases, such as cardiovascular disease, cancer, diabetes and weight gain. There is normally
a tight control over the H+ concentration, where pH is normally maintained between 7.35 – 7.45.
Metabolic acid production (e.g. sulphuric and phosphoric) and H+ intake must be balanced by acid
excretion. There are three central mechanisms that are involved in the removal of H+ and elimination
from the body
There are two classes of acids that are physiologically important, an sources of H+ are listed below:

Carbonic acids are gnerated from metabolism of fat and carbohydrates. They are potentially produced
from accumulation of CO2 in the body and are primarily eliminated by alveolar ventilation

Non-carbonic acids are generated from protein metabolism, and their elimination is a two-step
process. It involves the initial combination with extracellular bicarbonate and intracellular buffers to
minimise change in free hydrogen concentration. Then there is the subsequent excretion of acid by the
kidney
Defence against Shift in pH
 The first line of defence is the acid-base buffer systems.
 The secondary line of defence includes:
- Renal excretion of H+
- Respiratory excretion of CO2
 The respiratory centre responds to H+ increases in the following way:
- If pH is low (acidic), breathing can increase, thus removing H+
- If pH is high (basic), breathing can decrease, thus adding H+
1. Physiological Buffers
 Buffers are primarily weak acids, which are able to take up or release H+ so that changes in free H+
concentration are minimised. They are located in extracellular fluids, intracellular fluids and bone.
 Extracellular Buffers include:
- Bicarbonate/carbon dioxide buffer system


- Inorganic phosphates (plasma phosphate concentration of 1 mmol/L versus 24 mmol/L of HCO3-)
- Plasma proteins
HCO3- is the most important buffer in extracellular fluid:
- It is relatively high in concentration
- Ability to vary pCO2 via changes in alveolar ventilation
- Concentration is measurable
- Bicarbonate that is used in the buffering process must be regenerated to maintain normal acidbase balance. For example, acidaemia stimulates an increase in ventilation, which blunts the pH
change, but does not regenerate HCO3-.
- As these buffer systems are in equilibrium, altering the bicarbonate system will change body pH,
which resets the ratio of acid to base in the other buffers
- The lungs alter the bicarbonate system by altering PCO2 and the kidneys by altering the HCO3Intracellular and Bone Buffers
- These include proteins, organic and inorganic phosphate and haemoglobin.
- The bones are an important site for the buffering of acid and base loads
- An acid load, for example, is associated with the uptake of some of the excess H + ions by bone,
resulting in the release of buffer compounds, such as CaCO3 and CaHPO4, into the extracellular
fluid. This is demonstrated by decreased osteoblastic and increased osteoclastic function, resulting
in bone loss.
- The main intracellular buffers are sodium phosphate (Na 2HPO4/NaH2PO4) and proteins  proteins
can act as acids or bases because they contain both acidic and basic amino acid side chains
2. Renal Excretion of Hydrogen (Reabsorption of filtered HCO 3-)
Virtually all filtered HCO3- must be reabsorbed before dietary H+ load can be excreted
1. Intracellular H2O breaks down into H+ and OH- ions
2. OH- combines with CO2 to form HCO3- via a reaction catalysed by CA
3. In the proximal tubule, H+ ions are secreted into the lumen by the Na-H exchanger and HCO3- ions are
returned to systemic circulation by a Na+-3HCO3- cotransporter.
4. In collecting tubules, the processes are mediated by the active H+-ATPase pump and the Cl—HCO3exchanger.
5. Secreted H+ ions combined with the filtered HCO 3- to form H2CO3, and then CO2 and H2O, which are
passively reabsorbed. The dissociation of carbonic acid is facilitated when luminal carbonic anhydrase
is present.
The net effect is HCO3- reabsorption, although the HCO3- returned are not the same as those filtered. The
collecting tubules also have H+-K+-ATPase pumps in the luminal membrane, which are involved in both acid
secretion and K+ reabsorption.
Ammonia Handling and Acid-Base Balance
 Tubular cells, principally those in the proximal tubule, metabolise glutamine to produce ammonia and,
ultimately, glucose and bicarbonate
 The bicarbonate enters the blood and the NH4+ ions (which effectively carry a H + ion) are excreted in
the urine
 NH3 enters the filtrate from the tubular cells by simple diffusion or by the Na +/H+ exchanger, which can
also transport NH4+  once in the lumen, NH3 is protonated to NH4+, which cannot diffuse out of the
tubules
 In the thick ascending limb of the loop of Henle, NH4+ can be transported out of the lumen in place of
K+ on the NaK2Cl co-transporter
 Also, as the tip of the loop of Henle is alkaline, NH4+ in the filtrate dissociates to form NH3 and this
diffuses into the interstitium
 Secreted protons may also combine with ammonia  either way, this ultimately results with the
addition of acid to the tubular fluid and the extraction of acid from the ECF
Acid-Base Disorders


Acidosis is a process that tends to lower extracellular fluid pH.
- Metabolic – low pH and low HCO3- concentration
- Respiratory – low pH and high pCO2
Alkalosis is a process that tends to raise the extracellular fluid pH.
- Metabolic – high pH and high HCO3- concentration
- Respiratory – high pH and low pCO2
Potassium Balance





Potassium is the major intracellular cation, with an intracellular concentration of around 150 mmol/L,
compared with around 4 mmol/L in ECF.
To maintain potassium balance, the kidney excretes only 5-15% of filtered potassium. Potassium, like
sodium, is freely filtered in the glomerulus, but is handled quite differently in the tubule. Almost all the
filtered potassium is reabsorbed before the filtrate reaches the collecting tubules, where any
potassium that is to be excreted is then secreted into the collecting duct
In order to maintain appropriate intracellular potassium concentration, all cells use a pump-leak
mechanism. This consists of the Na+/K+ ATPase pump (major driving force behind potassium
movement) which actively transports potassium into the cell, balanced by various channels which
allow potassium to leak out of the cell. Intracellular potassium can be controlled by changing the
activity of the pump or by altering the number of permeability of the potassium channels
Potassium regulation takes place in two steps
- Initial uptake of some of the ingested potassium into cells, limiting rise in plasma potassium
concentration after ingestion
- Subsequent excretion of excess potassium in the urine – within 6-8 hours
Potassium uptake by cells- In normal people, 3 factors are significant in promoting potassium uptake
by cells
- Small elevation in plasma potassium concentration
- Insulin
- Adrenalin (epinephrine)
 Basal levels of insulin and adrenalin maintain activity of Na-K-ATPase pump and increases in
either hormone STIMULATES pump activity
 Adrenalin released during stress response can also significantly drive potassium into luminal
cells and lower plasma [K+]




Urinary potassium excretion
- Urinary potassium is NOT from glomerular filtration
- Almost all filtered potassium is reabsorbed passively in the proximal tubule and thick ascending
limb of the loop of Henle. The rate of potassium excretion being primarily determined by potassium
secretion from the cell into the lumen in the principal cells in the cortical collecting tubule and
outer medullary collecting tubule
Potassium secretion occurs through selective potassium channels in the apical membrane
- This selective process is enhanced by reabsorption of sodium through selective sodium channels in
the apical membrane
- Removal of sodium from lumen creates a lumen-negative electrical potential that promotes
potassium SECRETION through the apical potassium channels AND CHLORIDE REABSORPTION
between cells across the tight junction
Aldosterone plays central role in regulation of potassium excretion
- A small rise in plasma K+ is enough to increase the adrenal release of aldosterone
- Aldosterone then enters the potassium-secreting cell in the distal nephron and combines with its
cytosolic receptor – this complex then migrates to nucleus where it initiates synthesis of
aldosterone induced proteins
- Aldosterone enhances potassium secretion by affecting each of the steps involved in this process
Distal delivery of water and sodium
- At a constant aldosterone and plasma [K+], increasing sodium delivery (eg loop diuretic) will tend to
enhance distal sodium re-absorption and THEREFORE potassium EXCRETION
- Converse applies – decreased distal delivery of Na+ will diminish potassium secretion =
predisposing to hyperkalemia
Consequences of Hyperkalemia
The normal plasma potassium concentration is 3.5-5.0 mmol/L. As potassium is the main determinant of
the resting membrane potential of excitable cells, disturbances of plasma potassium can cause cardiac
dysrhythmias or arrest. Hyperkalaemia usually represents reduced urinary potassium excretion or, less
commonly, acute release from cells or a failure to enter cells. Hyperkalaemia does not persist unless there
is impaired renal excretion
Causes
 Shifts Out of Cells:
- During metabolic acidosis, H+ ions enter cells to be buffered and K + ions leave the cells to maintain
electroneutrality
- Insulin deficiency in diabetic ketoacidosis allows the net movement of potassium out of the cells
- Rhabdomyolosis or tissue destruction, or lysis such as that caused by chemotherapy, can cause
massive potassium loss from cells
 Failure of Renal Secretion:
- In renal failure, potassium accumulates because of the reduced number of nephrons capable of
potassium excretion
 Other Causes of Hyperkalaemia:
- Trimethoprim and pentamidine therapy can both can block K+ secretion in the collecting tubule
- Hypoaldosteronism- inadequate renin release, inadequate aldosterone release, or tubular
resistance to aldosterone. It is usually caused by potassium-sparing diuretics hyporeninemic
Treatment
 The patient should be placed on a cardiac monitor. If there are any ECG changes, urgent treatment is
essential
 Initially, calcium, given as calcium gluconate or calcium chloride, will antagonise the effects of
potassium on the cardiac action potential, but this is short-lived
 In the intermediate term, potassium can be shifted into cells by administering insulin, combined with
glucose, to prevent hypoglycaemia. β2 agonists can also be used for this purpose. Administration of
sodium bicarbonate produces a temporary alkalosis which also promotes the intracellular movement of
potassium
 In the longer term, excess potassium must be removed from the body. Diuretics, such as furosemide,
combined with hydration encourage renal excretion. If renal function is severely impaired, dialysis or
haemofiltration will remove potassium. Cation exchange resins such as sodium polystyrene sulfonate
can be given orally or rectally and bind potassium in the guy, exchanging it for sodium
Describe the mechanisms involved in fluid and electrolyte balance, thirst and salt appetite


The normal sodium intake in a Western diet is 150-200 mmol/L and 95 mmol/day recommended for a
healthy heart
The normal potassium intake is 60-80 mmol/day or 200-400 mmol/day on a vegetarian diet
 For the average 70kg male, the daily fluid intake should be around 2.5 L.
Disturbances to the normal electrolyte balance can result in the following symptoms:
 Thirst
 Muscle weakness
 Neurological impairment
(Hallucination,
 Decreased skin turgor
Delirium, Seizures)
 Haemodynamic effects
 Cardiac disturbances – ECG changes
 High risk of falls
Volume Homeostasis- Osmoreceptor (ADH Feedback System)



When osmolarity (plasma sodium concentration) increases above normal because of water deficit
(hypernatremia), for example, a feedback system kicks in. The hypothalamic osmoreceptors which
release ADH are stimulated by hyperosmolality and inhibited by hypoosmolality.
Large hypothalamic cells around the third ventricle send their axons directly to the posterior pituitary,
where the axon terminals release oxytocin and vasopressin (ADH) into the bloodstream.
ADH secretion is influenced by several factors (note that anything that stimulates ADH secretion also
stimulates thirst):
1. By special receptors in the hypothalamus that are sensitive to increasing plasma osmolarity (when
the plasma gets too concentrated). These stimulate ADH secretion.
2. By stretch receptors in the atria of the heart, which are activated by a larger than normal volume
of blood returning to the heart from the veins. These inhibit ADH secretion, because the body
wants to rid itself of the excess fluid volume.
3. By stretch receptors in the aorta and carotid arteries, which are stimulated when blood pressure
falls. These stimulate ADH secretion, because the body wants to maintain enough volume to
generate the blood pressure necessary to deliver blood to the tissues.



ADH (vasopressin) is transported to all parts of the body by the circulation, but the major site of action
is the kidneys. In the collecting duct, it bind to the V2 receptors on the principal cells of the collecting
duct, causing an increase in water permeability by inducing water channels (aquaporin’s) stored in
intracellular vesicles to fuse with the luminal membrane.
The effect on water permeability is graded- the higher the ADH concentration, the more receptor sites
occupied and the greater the water permeability. The increased water permeability in the distal
nephron segments causes increased water reabsorption and excretion of a small volume of
concentrated urine
ADH also increases the urea permeability of the collecting duct principal cells. Furthermore, ADH has a
rapid action and rapid turnover (10-20 minutes).
Renal Sodium Handling
Tubular reabsorption of Na
AII
Sympathetic tone
Unloading of baroreceptors
Aldosterone
Renin release
ECFV Contraction
NORMAL ECFV
ECFV expansion
ANF
Dopamine
Renal perfusion pressure
Renal interstitial hydrostatic pressure
Renal
prostaglandins
Tubular reabsorption of Na





Sodium is the major extracellular cation and its concentration is tightly controlled
Sodium and chloride ions are freely filtered in the glomerulus, so the concentration of these ions in the
filtrate is similar to that in blood (135-145mmol/L)
The kidney reabsorbs a huge amount of salt in the proximal tubules and the loop of Henle, and the
little that is left is reabsorbed in a precisely regulated manner by the distal tubules and collecting
ducts to maintain accurate salt balance. About 5% of salt intake is also lost in faeces and sweat
The basolateral membranes of the tubular cells contain Na+/K+ ATPases that actively pump sodium
into the peritubular plasma. From here, they pass freely into the blood to complete the reabsorption
process
The continual pumping of sodium out of cells and its subsequent removal by the blood creates a Na +
gradient between the tubular filtrate and the cell cytoplasm. This gradient allows Na + from the filtrate
to enter the cells passively at their apical membrane, provided that suitable channels or transporters
are present
Role of Thirst in Controlling Extracellular Fluid Osmolarity and Sodium Concentration


The kidneys minimize fluid loss during water deficits through the osmoreceptor-ADH feedback system.
Adequate fluid intake, regulated by the thirst mechanism, is necessary to counterbalance whatever
fluid loss does occur through sweating and breathing and through the gastrointestinal tract.
Central Nervous System Centres for Thirst


The same area along the anteroventral wall of the third ventricle that promotes ADH release also
stimulates thirst. Located anterolaterally in the preoptic nucleus is another small area that, when
stimulated electrically, causes immediate drinking that continues as long as the stimulation lasts. All
these areas together are called the thirst centre.
The neurons of the thirst centre respond to injections of hypertonic salt solutions by stimulating
drinking behaviour. These cells almost certainly function as osmoreceptors to activate the thirst
mechanism, in the same way that the osmoreceptors stimulate ADH release. Increased osmolarity of
the cerebrospinal fluid in the third ventricle has essentially the same effect to promote drinking.
Stimuli for Thirst




One of the most important is increased extracellular fluid osmolarity, which causes intracellular
dehydration in the thirst centres, thereby stimulating the sensation of thirst. This helps to dilute
extracellular fluids and returns osmolarity toward normal.
Decreases in extracellular fluid volume and arterial pressure also stimulate thirst by a pathway that is
independent of the one stimulated by increased plasma osmolarity. Thus, blood volume loss by
hemorrhage stimulates thirst even though there might be no change in plasma osmolarity. This
probably occurs because of neutral input from cardiopulmonary and systemic arterial baroreceptors
in the circulation.
A third important stimulus for thirst is angiotensin II.. Because angiotensin II is also stimulated by
factors associated with hypovolemia and low blood pressure, its effect on thirst helps to restore blood
volume and blood pressure toward normal, along with causing the kidneys to decrease fluid excretion.
Dryness of the mouth and mucous membranes of the esophagus can elicit the sensation of thirst.
Salt-Appetite Mechanism for Controlling Extracellular Fluid Sodium Concentration and
Volume



Maintenance of normal extracellular fluid volume and sodium concentration requires a balance
between sodium excretion and sodium intake. Nowadays, most people eat far more sodium than is
necessary for homeostasis, and there is evidence that our usual high sodium intake may contribute to
cardiovascular disorders such as hypertension.
There is also a regulatory component to salt appetite in which there is a behavioural drive to obtain
salt when there is sodium deficiency in the body.
In general, the two primary stimuli that are believed to increase salt appetite are
- Decreased extracellular fluid sodium concentration
- Decreased blood volume or blood pressure, associated with circulatory insufficiency
Describe the volume and composition of body fluid compartments and principles of
rehydration therapy
Overview



The total body fluid is distributed mainly between the extracellular fluid and the intracellular fluid
- The extracellular fluid is divided into the interstitial fluid and the blood plasma
- There is also another small compartment of fluid that is referred to as transcellular fluid. This
compartment includes fluid in the synovial, peritoneal, pericardial, and intraocular spaces, as well
as the cerebrospinal fluid
In the average 70-kilogram adult human, the total body water is about 60 % of the body weight (~42
litres). This percentage can change, depending on age, gender, and degree of obesity
As a person grows older, the percentage of total body weight that is fluid gradually decreases. This is
due in part to the fact that aging is usually associated with an increased percentage of the body weight
being fat, which decreases the percentage of water in the body
Intracellular Fluid Compartment


The intracellular fluid constitutes about 40% of the total body weight in an “average” person.
The fluid of each cell contains its individual mixture of different constituents, but the concentrations of
these substances are similar from one cell to another, and it is for this reason, the intracellular fluid of
all the different cells together is considered to be one large fluid compartment.
Extracellular Fluid Compartment


All the fluids outside the cells are collectively called the extracellular fluid. Together these fluids
account for about 20% of the body weight, or about 14 liters in a normal 70 kg adult
The two largest compartments of the extracellular fluid are the interstitial fluid, which makes up more
than three fourths of the extracellular fluid, and the plasma, which makes up almost one fourth of the
extracellular fluid, or about 3 litres.
Constituents of Extracellular and Intracellular Fluids

Comparisons of the composition of the extracellular fluid, including the plasma and interstitial fluid,
and the intracellular fluid are shown in this graph below:
Rehydration Therapy



The aim is to re-establish body fluid homeostasis from a current state of imbalance e.g. in dehydration
(hypovolemia) or an oedematous state (hypervolemia)
In oedematous patients, hypertonic solutions are sometimes infused into the bloodstream to draw
out excess water out of the extracellular space and move it into the bloodstream for kidney excretion.
Water is drawn out of the extracellular space due to the process of osmosis, it wants to move down a
concentration gradient to create an equilibrium with the hypertonic solution
In dehydrated patients, hypotonic solutions may be used to rehydrate their tissues. They are already
hypertonic due to the increased concentration of solutes within their body fluid, and hence a hypotonic
(i.e. dilute) solution can be used to reach an iso-osmotic state again



There are also other situations involving rehydration which have other special considerations:
- Haemorrhage treat with infusion of whole blood or a combination of red cells and plasma
substitute (e.g. Haemacel)
- Plasma loss (i.e. burns) treat with human plasma or plasma substitute
- Loss of water and electrolytes (i.e. vomiting, diarrhoea or excessive renal losses) treat with oral
replacement of water and sodium salts. Also, IV fluids may be required – rapid infusion (1000ml/hr)
is necessary if there is hypotension and/or evidence of impaired organ perfusion.
Fluid replacement must always be monitored, particularly in patients suffering from severe
hypovolaemia, as overly aggressive rehydration may result in circulatory overload i.e. blood vessels
don’t vasodilate quick enough.
Also, in any rehydration therapy, solute and electrolyte composition of the replacing fluid should be
selected appropriately to maintain osmotic equilibrium between body fluid compartments.
Describe the categories of renal failure (prerenal, renal and postrenal) and the immediate
consequences of acute renal failure
Overview
Acute renal failure
Prerenal
Intrinsic
Tubular
Acute tubular necrosis
Postrenal
Glomerular
Vascular
Glomerulonephritis
Vasculitis
Ischaemic
Toxic
Interstitial nephritis



Renal failure generally refers to any impairment in the glomerular filtration rate. A fall in GFR with
intrinsic renal disease usually reflects disease progression with reduction in number of functioning
nephrons
Acute renal failure is characterised by:
- Decreased renal perfusion
- Ischemic, toxic or obstructive insult to the renal tubule
- Inflammation and oedema of tubule
The causes of acute renal failure can be divided into three main categories- prerenal, postrenal and
intra-renal
- Acute renal failure resulting from decreased blood supply to the kidneys; this condition is often
referred to as prerenal acute renal failure to reflect the fact that the abnormality occurs in a
system before the kidneys. This can be a consequence of heart failure with reduced cardiac output
and low blood pressure or conditions associated with diminished blood volume and low blood
pressure, such as severe haemorrhage
- Intra-renal (renal) acute renal failure resulting from abnormalities within the kidney itself,
including those that affect the blood vessels, glomeruli, or tubules
-
Post-renal acute renal failure, resulting from obstruction of the urinary collecting system
anywhere from the calyces to the outflow from the bladder. The most common causes of
obstruction of the urinary tract outside the kidney are kidney stones, caused by precipitation of
calcium, urate, or cystine.
Prerenal Acute Renal Failure





Decreased renal blood flow is usually accompanied by decreased GFR and decreased urine output of
water and solutes.
- Oliguria, which refers to diminished urine output below the level of intake of water and solutes,
can occur. This causes accumulation of water and solutes in the body fluids.
- If renal blood flow is markedly reduced, total cessation of urine output can occur, a condition
referred to as anuria.
As long as renal blood flow does not fall below 20-25%of normal, acute renal failure can usually be
reversed if the cause of the ischemia is corrected before damage to the renal cells has occurred.
Unlike some tissues, the kidney can endure a relatively large reduction in blood flow before actual
damage to the renal cells occurs
The reason for this is that as renal blood flow is reduced, the GFR and the amount of sodium chloride
filtered by the glomeruli (as well as the filtration rate of water and other electrolytes) are reduced. This
decreases the amount of sodium chloride that must be reabsorbed by the tubules, which uses most
of the energy and oxygen consumed by the normal kidney. Therefore, as renal blood flow and GFR fall,
the requirement for renal oxygen consumption is also reduced.
When blood flow is reduced below this basal requirement, which is usually less than 20 to 25 per cent
of the normal renal blood flow, the renal cells start to become hypoxic, and further decreases in renal
blood flow, if prolonged, will cause damage or even death of the renal cells, especially the tubular
epithelial cell
If the cause of prerenal acute renal failure is not corrected and ischemia of the kidney persists longer
than a few hours, this type of renal failure can evolve into intra-renal acute renal failure.
Intra-renal Acute Renal Failure



Includes abnormalities that originate within the kidney and that abruptly diminish urine output
This category of acute renal failure can be further divided into
- Conditions that injure the glomerular capillaries or other small renal vessels
- Conditions that damage the renal tubular epithelium
- Conditions that cause damage to the renal interstitium
This type of classification refers to the primary site of injury, but because the renal vasculature and
tubular system are functionally interdependent, damage to the renal blood vessels can lead to tubular
damage, and primary tubular damage can lead to damage of the renal blood vessels.
Acute Renal Failure Caused by Glomerulonephritis
 Acute glomerulonephritis is a type of intra-renal acute renal failure usually caused by an abnormal
immune reaction that damages the glomeruli
 In about 95% of the patients with this disease, damage to the glomeruli occurs 1 to 3 weeks after an
infection elsewhere in the body, usually caused by certain types of group A-beta streptococci, i.e. sore
throat, tonsillitis, skin infection
- It is not the infection itself that damages the kidneys;
- Over a few weeks, as antibodies develop against the streptococcal antigen, the antibodies and
antigen react with each other to form an insoluble immune complex that becomes entrapped in
the glomeruli, especially in the basement membrane portion of the glomeruli
- Once the immune complex has deposited in the glomeruli, many of the cells of the glomeruli begin
to proliferate, and large numbers of white blood cells become entrapped in the glomeruli
- Many of the glomeruli become blocked by this inflammatory reaction, and those that are not
blocked usually become excessively permeable, allowing both protein and red blood cells to leak
from the blood of the glomerular capillaries into the glomerular filtrate
 The acute inflammation of the glomeruli usually subsides in about 2 weeks, and in most patients, the
kidneys return to almost normal function within the next few weeks to few months
 Sometimes, however, many of the glomeruli are destroyed beyond repair, and in a small percentage
of patients, progressive renal deterioration continues indefinitely, leading to chronic renal failure
Tubular Necrosis as a Cause of Acute Renal Failure
 Tubular necrosis is the destruction of epithelial cells in the tubules.
 Acute Tubular Necrosis Caused by Severe Renal Ischemia:
- If the ischemia is severe enough to seriously impair the delivery of nutrients and oxygen to the
renal tubular epithelial cells, and if the insult is prolonged, damage or eventual destruction of the

epithelial cells can occur.
- When this happens, tubular cells “slough off” and plug many of the nephrons, so that there is no
urine output from the blocked nephron. The affected nephrons often fail to excrete urine even
when renal blood flow is restored to normal, as long as the tubules remain plugged
- The most common causes of ischemic damage to the tubular epithelium are the prerenal causes of
acute renal failure associated with circulatory shock
Acute Tubular Necrosis Caused by Toxins or Medications:
- These substances have specific toxic actions on the renal tubular epithelial cells, causing death of
many of them
- As a result, the epithelial cells slough away from the basement membrane and plug the tubules
- In some instances, the basement membrane also is destroyed
- If the basement membrane remains intact, new tubular epithelial cells can grow along the surface
of the membrane, so that the tubule repairs itself within 10 to 20 days.
Post-renal Acute Renal Failure
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Multiple abnormalities in the lower urinary tract can block or partially block urine flow and therefore
lead to acute renal failure even when the kidneys’ blood supply and other functions are initially normal
If the urine output of only one kidney is diminished, no major change in body fluid composition will
occur because the contralateral kidney can increase its urine output sufficiently to maintain relatively
normal levels of extracellular electrolytes and solutes as well as normal extracellular fluid volume.
With this type of renal failure, normal kidney function can be restored if the basic cause of the problem
is corrected within a few hours
Chronic obstruction of the urinary tract, lasting for several days or weeks, can lead to irreversible
kidney damage. Some of the causes of post-renal acute failure include:
- Bilateral obstruction of the ureters or renal pelvises caused by large stones or blood clots
- Bladder obstruction
- Obstruction of the urethra
If the urinary tract is obstructed (e.g. by stones or prostate enlargement), hydrostatic pressure in
Bowman’s space increases and consequently GFR decreases. A very high rate of urine output also may
be accompanied by an increase in hydrostatic pressure in Bowman’s space and a decrease in GFR
because an increased pressure head is required to force a large volume flow down tubules and
collecting ducts.
Physiologic Effects of Acute Renal Failure
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A major physiologic effect of acute renal failure is retention in the blood and extracellular fluid of
water, waste products of metabolism, and electrolytes  this can lead to water and salt overload,
which in turn can lead to oedema and hypertension.
Excessive retention of potassium, however, is often a more serious threat to patients with acute renal
failure, because increases in plasma potassium concentration (hyperkalaemia) to more than about
twice normal can be fatal. Because the kidneys are also unable to excrete sufficient hydrogen ions,
patients with acute renal failure develop metabolic acidosis, which in itself can be lethal or can
aggravate the hyperkalaemia.
In the most severe cases of acute renal failure, complete anuria occurs. The patient will die in 8 to 14
days unless kidney function is restored or unless an artificial kidney is used to rid the body of the
excessive retained water, electrolytes, and waste products of metabolism.
Describe the anatomical relationships of the prostate gland and the effect of prostatic
enlargement on urinary outflow
Structure of the Prostate Gland
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The prostate (approximately 3 cm long, 4 cm wide, and 2 cm in depth) is the largest accessory gland of
the male reproductive system. It is a single, firm, doughnut-shaped retroperitoneal organ that
encircles the neck of the bladder and urethra just inferior to bladder.
Two-thirds of the prostate is glandular, and the rest is fibromuscular
The fibrous capsule of the prostate is dense and neurovascular, incorporating the prostatic plexuses of
veins and nerves. All this is surrounded in turn by the visceral layer of the pelvic fascia, forming a
fibrous prostatic sheath that is thin anteriorly, continuous anterolaterally with the puboprostatic
ligaments, and dense posteriorly where it blends with the rectovesical septum
Fluid from prostate plays a role in :
- Activating sperm
- 1/3 of semen volume
- It is milky and slightly acidic which contains citrate (nutrients), enzymes, and PSA (prostate specific
agent)
- The secretion from the prostatic gland leaves when the smooth muscle contracts during
ejaculation
The prostate has:
- A base closely related to the neck of the bladder.
- An apex that is in contact with fascia on the superior aspect of the urethral sphincter and deep
perineal muscles.
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A muscular anterior surface, featuring mostly transversely oriented muscle fibers forming a
vertical, trough-like hemisphincter (rhabdosphincter), which is part of the urethral sphincter,
separated from the pubic symphysis by retroperitoneal fat in the retropubic space.
- A posterior surface that is related to the ampulla of the rectum.
- Inferolateral surfaces that are related to the levator ani.
Although not clearly distinct anatomically, the following lobes of the prostate are traditionally
described:
- The isthmus of the prostate (commissure of prostate; historically, the anterior) lies anterior to the
urethra. It is fibromuscular, the muscle fibres representing a superior continuation of the urethral
sphincter muscle, and contains little, if any, glandular tissue.
- The inferoposterior (posterior) lobe lies posterior to the urethra and inferior to the ejaculatory
ducts; it is readily palpable by digital rectal examination.
- The right and left (lateral) lobes on either side of the urethra form the major part of the prostate.
- The middle (median) lobe lies between the urethra and the ejaculatory ducts and is closely related
to the neck of the bladder. Enlargement of the middle lobe is believed to be at least partially
responsible for the formation of the uvula that may project into the internal urethral orifice.
Benign Prostatic Hyperplasia (BPH)
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From 40 yrs of age, the prostate increases by 2.4cm3 per year on average
Characterised by hyperplasia of prostatic stromal and epithelial cells, resulting in the formation of
large, fairly discrete nodules in the periurethral region of prostate. When sufficiently large, the
nodules compress and narrow the urethral canal causing partial or complete obstruction of the
urethra. This results in:
- Compression of urethra with difficulty in urination
- Retention of urine in the bladder with subsequent distension and hypertrophy of the bladder,
infection of the urine, development of cystitis and renal infections.
The middle lobe usually enlarges the most and obstructs the internal urethral orifice. The more the
person strains, the more the valve-like prostatic mass occludes the urethra
If the urinary tract is obstructed (e.g. by stones or prostate enlargement), hydrostatic pressure in
Bowman’s space increases and consequently GFR decreases. A very high rate of urine output also may
be accompanied by an increase in hydrostatic pressure in Bowman’s space and a decrease in GFR
because an increased pressure head is required to force a large volume flow down tubules and
collecting ducts.
Symptoms include – hesitancy, poor prolonged flow, sensation of incomplete emptying, and overflow
dribbling.
Secondary (irritative) symptoms – urinary frequency, nocturia, urgency of micturition and urge
incontinence (sudden and strong need to urinate)not specific to BPH.
Long-term consequences- Hydronephrosis (swelling of a kidney due to build-up of urine) or acute
retention with secondary UTI, azotemia or uremia (urea in bloow) may develop.
Secondary changes in the bladder e.g. hypertrophy, trabeculation (dense collagenous tissue) and
diverticulum formation.
Treatment – medical or surgical therapy e.g. decreasing fluid intake, esp prior to bedtime; moderating
intake of alcohol and caffeine-containing products, following timed voiding schedules. Most commonly
used and effective medical therapy is α-blockers which decrease prostate smooth muscle tone via
inhibition of α1-adrenergic receptors.
Urinalysis
The ‘normal’ colour for urine is straw-yellow. Abnormalities are :
 Cloudy – usually due to the presence of white blood cells, bacteria, mucus, RBCs, fat, epithelial cells or
phosphates. It is seen in UTIs.
 Dark – characteristic of liver disorders such as hepatitis or cirrhosis.
 Red/Pink – can be due to beets or food colouring, or bleeding from UTIs, enlarged prostate, kidney
cancer, bladder tumor, tuberculosis, bladder stones, kidney infection, Wilms' tumor (in children), or
hypernephroma (tumour resembling adrenal cortex in kidney). Hemolytic anemia and porphyria can
also cause urine to take on these colors. It may also occur after trauma to the kidneys or urinary tract.
 Dark yellow/orange – use of laxatives, excess carotene consumption
NSAIDs
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The relevance of NSAIDs to renal failure is great because they are capable of inducing allergic
interstitial nephritis. This is characterized by oedema and cellular infiltrate within the interstitium. This
allergic interstitial nephritis has several other unusual features, in that some drugs, particularly
fenoprofen, also induce profuse proteinuria which may provoke a full nephrotic syndrome. The renal
failure induced may also be irreversible.
Their effects on renal blood flow- In any state of renal underperfusion, like mild cardiac
decompensation, volume depletion, salt loss, cirrhosis or a nephrotic syndrome, NSAIDs may cause a
profound fall in renal bloodflow and in glomerular filtration.
The precise mechanism underlying this dangerous effect is not entirely clear, but it appears that
vasodilator prostaglandins- principally PGI2 (prostacyclin). This prostaglandin usually helps, in states of
renal hypoperfusion, to maintain cortical bloodflow and glomenrular filtration through effects on the
intrarenal distribution of blood.
NSAIDs act by reducing prostaglandin biosynthesis through inhibition of cyclooxygenase (COX) which
exists as two isoforms (COX-1 and COX-2). Drugs that selectively inhibit COX-2 might be expected to
produce effects on renal function similar to nonselective NSAIDs which inhibit both COX-1 and COX-2.
Class Learning Objectives
 Kidney response to reduced renal perfusion
 RAAS, ADH – effects of ACE inhibitors on this system
 Impact on electrolyte loss
 Acid-base balance & potassium balance in kidney and hyperkalemia
 PGI2 role of prostaglandins in Kidneys
 Mechanisms by which normal BP is maintained (Renal and Cardiac including ANP)
 Relation of Prostate to Kidney and urinary flow
 Urinalysis
 Osmolarity
 Anatomical and physiological determinants of glomerular filtration rate and renal blood flow.
 Function of the renal tubules, i.e. reabsorption, secretion and urine concentration.
 Categories of renal failure (prerenal, renal and postrenal) and the immediate consequences of acute
renal failure.
 The anatomical relationships of the prostate gland and the effect of prostatic enlargement on urinary
outflow.
Official Learning Objectives
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Describe the anatomical and physiological determinants of glomerular filtration rate and renal blood
flow
Describe the function of the renal tubules, i.e. Reabsorption, secretion and urine concentration
Describe the renal actions and regulation of the renin-angiotensin system, prostaglandins and atrial
natriuretic peptide
Describe the role of the kidney in acid-base and potassium balance, and the consequences of
hyperkalaemia
Describe the mechanisms involved in fluid and electrolyte balance, thirst and salt appetite
Describe the volume and composition of body fluid compartments and principles of rehydration
therapy
Describe the categories of renal failure (prerenal, renal and postrenal) and the immediate
consequences of acute renal failure
Describe the anatomical relationships of the prostate gland and the effect of prostatic enlargement on
urinary outflow.
Keywords and Phrases
Acidosis, Anion-gap, Acute tubular necrosis, Acute renal failure, Back pain. Dehydration, Uraemia,
Diarrhoea, Renal tubular secretion and reabsorption, Osmolality, Specific gravity, Prerenal renal failure,
Postural hypotension, Renal blood flow (RBF), Glomerular filtration rate (GFR), Urine concentration,
Urinalysis, Prostate, Renal Casts, Nephrotoxicity, Urine microscopy, Oliguria, ACE inhibitor, Angiotensin,
Renin, Antidiuretic hormone, Fluid and electrolyte balance, Prostatic hypertrophy, Tissue turgor, JVP
Drugs Used
Naproxen, Lisinopril